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Anti-cytotoxic T lymphocyte antigen-4 (CTLA-4) immunotherapy for the treatment of prostate cancer
Abstract
Costimulatory pathway ligands and receptors can deliver either positive or negative signals to help determine the ultimate fate of activated T lymphocytes. Cytotoxic T lymphocyte antigen-4 (CTLA-4) represents one of the most extensively studied receptors in the costimulatory pathway and has recently been shown to function as a potent inhibitor of T cell-mediated immunity. T-cell expression of CTLA-4 indirectly facilitates tumor progression by restraining host antitumoral immunity. In contrast, administration of a monoclonal antibody to block CTLA-4 function can alleviate restraints on T-cell activity to promote immune-mediated tumor regression. We review the preclinical and clinical experience with CTLA-4 blockade as a promising immunotherapeutic approach to treat patients with advanced prostate cancer.
... It is this second costimulatory signal, which is antigen independent, that is critical for facilitating T-cell activation, sustaining T-cell proliferation, allowing for cellto-cell cooperation and the induction of differentiation from a naive to an effector or memory T-cell phenotype [4]. Underscoring the importance of costimulatory signaling, it has been demonstrated that transgenic mice lacking either the CD28 costimulatory receptor or B7 costimulatory ligands exhibit severe impairments in generating T-cell responses [5]. In addition to the B7–CD28 interaction, recent evidence suggests that the ultimate fate of an activated T cell is governed by a number of additional positive and negative costimulatory signals emanating from a variety of T-cell receptors interacting with their cognate ligands [6]. ...
... Ag: Antigen; CTLA: Cytotoxic T-lymphocyte antigen; TCR: T-cell receptor. Redrawn with permission from [5]. Monoclonal antibody blockade of CTLA-4 allows CD28 to interact with its B7-family counterreceptor , thus stimulating a tumor specific T-cell response. ...
... Ag: Antigen; APC: Antigenpresenting cell; CTLA: Cytotoxic T-lymphocyte antigen; TCR: T-cell receptor. Redrawn with permission from [5]. Photomicrograph at ×400. ...
T-cell costimulatory molecules deliver positive or negative signals to govern the ultimate fate of immune responses. These ligands and receptors that negatively costimulate T cells (including cytotoxic T-lymphocyte antigen [CTLA]-4, B7-H1, programmed death [PD]-1, B7-H3 and B7x) have received significant interest recently owing to their proposed ability to form a molecular shield for tumor cells. CTLA-4 represents the most extensively studied receptor in the costimulatory pathway and functions as a potent inhibitor of T-cell-mediated immunity. Clinical trials with anti-CTLA-4 are ongoing, although numerous objective responses have been observed in heavily pretreated patients, albeit with autoimmune side effects. In renal cell carcinoma, B7-H1, PD-1 and B7x have been observed to be expressed on tumor cells or infiltrating lymphocytes and are individually associated with adverse pathologic features and poor clinical outcome. In prostate cancer, B7-H3 and B7x immunostaining intensity correlate with disease spread, clinical cancer recurrence and cancer-specific death. External validation and prospective studies are now needed to confirm these findings, while further development of humanized monoclonal antibodies, similar to the experience with anti-CTLA-4, are underway. Herein, we review the B7-CD28 family as it applies to urologic malignancies.
... Along with programmed cell death 1 ligand 1 (PD-L1) and programmed cell death 1 (PD-1), there is another inhibitory mechanism. Cytotoxic antigen, which associated with T lymphocytes (CTLA4), can compete with CD80/86 and inhibit T cell activation [18]. After that, PD1, which are expressed on the surface of T cells, bind to PD-L1 and block immune responses. ...
... Drugs-inhibitors of immune checkpoints have made it possible to achieve certain successes in the immunotherapy of cancer patients. The checkpoint inhibitors CTLA1, PD1, and PDL is rapidly becoming a promising therapeutic area in RT, due to which it is proposed to increase antitumor immunity and increase the frequency of the abscopal effect [18]. The combination of radiation and immune therapy can potentially help overcome tumor-induced immunosuppression, which causes a lack of activating effect of RT on tumor-specific T cells. ...
This review is devoted to a rare in clinical practice, but promising phenomenon of regression distant non-irradiated metastases in combination therapy of cancer patients. R. H. Mole in 1953 suggested introducing the term “abscopal effect” to denote the effect of ionizing radiation “at a distance from the irradiated volume but within the same organism.” Currently, it is a hypothesis in the treatment of metastatic cancer, when there is a regression of untreated areas simultaneously with a decrease in the tumor. After the discovery of immune checkpoint cases were increase with patients treated with check-point blockade (especially lymphocyte associated protein 4, programmed cell death 1/programmed cell death 1 ligand 1) and which have an abscopal effect. This review systematizes works covering the time period from 1969 to 2019, which give cases of the abscopal effect at different localizations. However, abscopal effect is a poorly understood phenomenon. In this review, the authors tried to collect all information about the possible mechanisms of the abscopal effect, possible role in antitumor response and frequency abscopal effect at radio/immunotherapy or combined both.
... Sipuleucel-T was the first therapeutic vaccine to be approved by the United States Food and Drug Administration (FDA) for patients with metastatic castration-resistant prostate cancer (mCRPC) based on the pivotal phase III IMPACT trial [19], and the first autologous cellular therapeutic vaccine for any cancer. While checkpoint inhibitors (CPI) immunotherapy has vastly improved the outcomes of patients with malignancies such as melanoma and non-small cell lung cancer, its efficacy in patients with prostate cancer to date has been modest [20][21][22]. ...
... Due to CPI monotherapy's limited activity in prostate cancer [20,21], there has been enthusiasm for combining these agents with tyrosine kinase inhibitors (TKIs) [149]. TKIs compete with the adenosine triphosphate (ATP) binding site of the catalytic domain of oncogenic tyrosine kinases [150]. ...
Simple Summary
Immunotherapy has changed the treatment paradigm of numerous malignancies such as non-small cell lung cancer and melanoma. To date, there has been only modest demonstrable efficacy of immunotherapy for prostate cancer. This lack of efficacy is likely due to the immunosuppressive tumor microenvironment. When we consider the fact that metastatic castrate-resistant state is the most lethal form of prostate cancer, there is an unmet need to increase the efficacy of immune therapies for this disease. The treatment paradigm has now shifted towards combinatorial regimens to enhance the anti-tumor immune response. These combinations with immunomodulatory agents in ongoing clinical trials include conventional agents such as chemotherapy and numerous novel agents. This review summarizes the clinical trials recruiting patients with metastatic castrate-resistant prostate cancer utilizing immunotherapeutic approaches.
Abstract
Although most prostate cancers are localized, and the majority are curable, recurrences occur in approximately 35% of men. Among patients with prostate-specific antigen (PSA) recurrence and PSA doubling time (PSADT) less than 15 months after radical prostatectomy, prostate cancer accounted for approximately 90% of the deaths by 15 years after recurrence. An immunosuppressive tumor microenvironment (TME) and impaired cellular immunity are likely largely responsible for the limited utility of checkpoint inhibitors (CPIs) in advanced prostate cancer compared with other tumor types. Thus, for immunologically “cold” malignancies such as prostate cancer, clinical trial development has pivoted towards novel approaches to enhance immune responses. Numerous clinical trials are currently evaluating combination immunomodulatory strategies incorporating vaccine-based therapies, checkpoint inhibitors, and chimeric antigen receptor (CAR) T cells. Other trials evaluate the efficacy and safety of these immunomodulatory agents’ combinations with standard approaches such as androgen deprivation therapy (ADT), taxane-based chemotherapy, radiotherapy, and targeted therapies such as tyrosine kinase inhibitors (TKI) and poly ADP ribose polymerase (PARP) inhibitors. Here, we will review promising immunotherapies in development and ongoing trials for metastatic castration-resistant prostate cancer (mCRPC). These novel trials will build on past experiences and promise to usher a new era to treat patients with mCRPC.
... Previous studies have demonstrated that a temporary delay in CLTA4 appearance on T-cell surface in immune synapses enhances the immune response. Thus, it was accepted that CTLA4 blockade can enhance immunity to tumors and may therefore be a potentially promising immunotherapeutic approach to treat patients with various cancer types (13)(14)(15)(16)(17)(18)(19)(20). ...
... However, different results were also reported in literature, which suggests the importance of dietary behavior or sustaining physiological conditions over CTLA4 such as the indirect generation of ROS by degradation of tryptophan via IDO. As explained, blockade of CTLA4 could be a potential immunotherapeutic approach to several cancer types by enhancing T-cell immonoreactivity as an antitumoral effect (9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20). On the other hand, our results show high oxidant and low antioxidant status may increase inflammation as a defense mechanism. ...
Background: Colorectal cancer (CRC) is the third most frequent cancer worldwide. Research has revealed the contributions of the immune system and anti-inflammatory pathways in the development of cancer. The balance between cluster of differentiation 28 (CD28) and cytotoxic Tlymphocyte- associated protein 4 (CTLA4) signaling is important for the regulation of immune responses. The oxidant-antioxidant balance by sustaining redox control via several defense mechanisms is also an important factor for the progression of cancer. The aim of the present study was to determine the distribution of CTLA4/CD28 variants and oxidant-antioxidant status in patients with CRC. Materials and Methods: This study enrolled 80 patients with CRC and 115 healthy controls. We used a spectrophotometric assay to detect the levels of lipid peroxidation products malon dialdehyde (MDA) and lipid hydroperoxide (LHP), and measured the concentration of protein damage products, advanced oxidation protein products (AOPP) and protein carbonyl (PCO). Additionally, antioxidant levels were detected by measuring copper, zinc, superoxide dismutase (Zn-Cu SOD) and total thiol (T-SH) levels, and advanced glycation end-products (AGEs). The CTLA4 -318C>T, CTLA4 49A>G and CD28C>T genotypes were determined by using restriction enzymes. Results: AOPP and PCO levels were increased in patients with CRC as well as those of LHP, MDA and AGE, while the levels of antioxidants such as Cu-Zn SOD and T-SH were lower. Lower serum levels of CTLA4 and higher serum levels of CD28 were detected in patients and, an association of the CTLA4 -318C/T polymorphism was found in patients with CRC. Conclusion: Our oxidative stress was increased in patients with CRC, suggesting the contribution of this disturbed oxidative status to serum CTLA4 and CD28 levels, and to the pathogenesis of CRC.
... It is well documented that downregulation of cell surface Her2/neu expression reverses transformed phenotypes and leads to a reduction in proliferation of tumor cells. Treatment of tumors with ATRA has been shown to exhibit increased sensitivity to MHC class I-restricted killing by CTL and NK-cell-mediated lysis [116, 117]. ATRA has also been shown to be beneficial in leukemia, cervical cancer, thyroid cancer, breast cancer, squamous cell carcinoma, skin cancer, and head and neck cancer when administered alone or in combination with other therapies [118]. ...
... ATRA also induces systemic modulation of antigen presentation by nonprofessional antigen presenting cells such as tumor cells. In addition, ATRA has been shown to modify the immunogenicity of tumor cells both in vitro and in vivo through differential regulation of MHC class I and intercellular adhesion molecule-1 (ICAM-1) [114, 117]. The upregulation of ICAM-1 may increase the sensitivity of glioblastoma to NK-cells. ...
Glioblastoma multiforme is the most invasive and aggressive brain tumor in humans, and despite the latest chemical and radiative therapeutic approaches, it is still scarcely sensitive to these treatments and is generally considered an incurable disease. This paper will focus on the latest approaches to the treatment of this cancer, including the new chemicals such as proautophagic drugs and kinases inhibitors, and differentiating agents. In this field, there have been opening new perspectives as the discovery of possible specific targets such as the EGFRvIII, a truncated form of the EGF receptor. Antibodies against these targets can be used as proapoptotic agents and as possible carriers for chemicals, drugs, radioisotopes, and toxins. In this paper, we review the possible mechanism of action of these therapies, with particular attention to the combined use of toxic substances (for example, immunotoxins) and antiproliferative/differentiating compounds (i.e., ATRA, PPARγ agonists). All these aspects will be discussed in the view of progress clinical trials and of possible new approaches for directed drug formulations.
... Several studies have reported that antibodies that block the activity of this key immunoregulatory molecule cause tumor shrinkage in patients with metastatic melanoma when administered along with a cancer vaccine (11)(12)(13). Preclinical and clinical trials have also shown that CTLA-4 blockade may be a promising immunotherapeutic approach to treat patients with other advanced cancers (14)(15)(16). These findings suggest that CTLA-4 may play an important role in cancer development and progression. ...
... These findings highlight the importance of antitumor T lymphocytes in immune surveillance of tumorigenesis. In the model of tumor-specific T-cell activation, accumulative evidence has documented that removal of CTLA-4mediated inhibition leads to enhancement of antitumor responses (1,6,10,(12)(13)(14)(15)(16)(17). However, whether genetic variations in CTLA-4 may influence T-cell activation in the immune response and thus affect susceptibility to cancer is largely unknown. ...
Antitumor T lymphocytes play a pivotal role in immunosurveillance of malignancy. The CTL antigen 4 (CTLA-4) is a vital negative regulator of T-cell activation and proliferation. This study examined whether genetic polymorphisms in CTLA-4 are associated with cancer susceptibility. A two-stage investigation using haplotype-tagging single nucleotide polymorphism approach and multiple independent case-control analyses was performed to assess the association between CTLA-4 genotypes and cancer risk. Functional relevance of the polymorphisms was examined by biochemical assays. We found that the 49G>A polymorphism in the CTLA-4 leading sequence causing (17)Ala to (17)Thr amino acid substitution is associated with increased susceptibility to multiple cancers, including lung, breast, esophagus, and gastric cardia cancers. Genotyping in 5,832 individuals with cancer and 5,831 control subjects in northern and southern Chinese populations showed that the CTLA-4 49AA genotype had an odds ratio of 1.72 (95% confidence interval, 1.50-2.10; P = 3.4 x 10(-7)) for developing cancer compared with the 49GG genotype. Biochemical analyses showed that CTLA-4-(17)Thr had higher capability to bind B7.1 and stronger inhibitory effect on T-cell activation compared with CTLA-4-(17)Ala. T cells carrying the 49AA genotype had significantly lower activation and proliferation rates compared with T cells carrying the 49GG genotype upon stimulation. These results are consistent with our hypothesis and indicate that genetic polymorphisms influencing T-cell activation modify cancer susceptibility.
... CTLA-4, also known as CD152, is a transmembrane protein expressed in activated CD4+ and CD8+ T cells (294)(295)(296)(297)(298). Under physiological conditions, CTLA-4 and CD80/CD86 binding can inhibit T-cell activation signals and prevent autoimmune disease (299,300). ...
Resistance to targeted therapy and immunotherapy in non-small cell lung cancer (NSCLC) is a significant challenge in the treatment of this disease. The mechanisms of resistance are multifactorial and include molecular target alterations and activation of alternative pathways, tumor heterogeneity and tumor microenvironment change, immune evasion, and immunosuppression. Promising strategies for overcoming resistance include the development of combination therapies, understanding the resistance mechanisms to better use novel drug targets, the identification of biomarkers, the modulation of the tumor microenvironment and so on. Ongoing research into the mechanisms of resistance and the development of new therapeutic approaches hold great promise for improving outcomes for patients with NSCLC. Here, we summarize diverse mechanisms driving resistance to targeted therapy and immunotherapy in NSCLC and the latest potential and promising strategies to overcome the resistance to help patients who suffer from NSCLC.
... CTLA-4 CTLA-4, also known as CD152, is a transmembrane protein expressed in activated CD4 + and CD8 + T cells. 134,[135][136][137][138] While CD28 was found to be a T-cell costimulatory molecule, 139 CTLA-4 was later discovered to mimic CD28 and act as a brake on T-cell activation. 140,141 Under physiological conditions, CTLA-4 and CD80/CD86 binding can inhibit T-cell activation signals and prevent autoimmune disease. ...
Cancers are highly complex diseases that are characterized by not only the overgrowth of malignant cells but also an altered immune response. The inhibition and reprogramming of the immune system play critical roles in tumor initiation and progression. Immunotherapy aims to reactivate antitumor immune cells and overcome the immune escape mechanisms of tumors. Represented by immune checkpoint blockade and adoptive cell transfer, tumor immunotherapy has seen tremendous success in the clinic, with the capability to induce long-term regression of some tumors that are refractory to all other treatments. Among them, immune checkpoint blocking therapy, represented by PD-1/PD-L1 inhibitors (nivolumab) and CTLA-4 inhibitors (ipilimumab), has shown encouraging therapeutic effects in the treatment of various malignant tumors, such as non-small cell lung cancer (NSCLC) and melanoma. In addition, with the advent of CAR-T, CAR-M and other novel immunotherapy methods, immunotherapy has entered a new era. At present, evidence indicates that the combination of multiple immunotherapy methods may be one way to improve the therapeutic effect. However, the overall clinical response rate of tumor immunotherapy still needs improvement, which warrants the development of novel therapeutic designs as well as the discovery of biomarkers that can guide the prescription of these agents. Learning from the past success and failure of both clinical and basic research is critical for the rational design of studies in the future. In this article, we describe the efforts to manipulate the immune system against cancer and discuss different targets and cell types that can be exploited to promote the antitumor immune response.
... Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) is a critical immune checkpoint that negatively regulates T cell activation of the immune system. It has been reported that CTLA-4 is overexpressed and correlated with poor prognosis in various types of cancer, including breast cancer [7], lung cancer [8], prostate cancer [9], and cervical cancer [10]. More recently, promising results were also shown by administration of CTLA-4 inhibitor in cancer treatment [11][12][13]. ...
Objective:
The purpose of this study was to evaluate the prognostic role of the cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) expression level and the platelet lymphocyte ratio (PLR) level in esophageal squamous cell carcinoma (ESCC) patients.
Methods:
84 ESCC patients who received surgical treatment in our hospital were enrolled in the study. The correlation of each biomarker's level with ESCC patients' clinicopathological characteristics and overall survival (OS) was assessed.
Results:
The elevated expression rate of T-CTLA-4 (tumor cell CTLA-4) and I-CTLA-4 (interstitial lymphocyte CTLA-4) was 48.8% and 44.0%, respectively. The number of enrolled patients with a higher PLR level (≥119) was 48. The prognostic value of T-CTLA-4, I-CTLA-4, and PLR in ESCC patients was not detected. However, patients with both a low T-CTLA-4 expression level and a low PLR level that had longer OS (p = 0.023) were found. The prognostic role of T-CTLA-4(-) +PLR (-) status in ESCC patients was also confirmed in multivariate analyses (p = 0.027).
Conclusion:
These results demonstrated the potential prognostic value of combined analysis of CTLA-4 and PLR in ESCC patients.
... Currently, three checkpoint inhibitors are approved for the treatment of advanced melanomas: ipilimumab, a CTLA-4-specific mAb (89), and pembrolizumab and nivolumab, which are PD-1-specific mAbs (11). Furthermore, remarkable clinical effectiveness has been reported in other cancers such as, ovarian (90) non-small cell lung carcinoma (91), breast (92), prostate (93), and lymphoma (94). ...
Currently, a marked number of clinical trials on cancer treatment have revealed the success of immunomodulatory therapies based on immune checkpoint inhibitors that activate tumor-specific T cells. However, the therapeutic efficacy of cancer immunotherapies is only restricted to a small fraction of patients. A deeper understanding of key mechanisms generating an immunosuppressive tumor microenvironment (TME) remains a major challenge for more effective antitumor immunity. There is a growing evidence that the TME supports inappropriate metabolic reprogramming that dampens T cell function, and therefore impacts the antitumor immune response and tumor progression. Notably, the immunosuppressive TME is characterized by a lack of crucial carbon sources critical for T cell function and increased inhibitory signals. Here, we summarize the basics of intrinsic and extrinsic metabolic remodeling and metabolic checkpoints underlying the competition between cancer and infiltrating immune cells for nutrients and metabolites. Intriguingly, the upregulation of tumor programmed death-L1 and cytotoxic T lymphocyte-associated antigen 4 alters the metabolic programme of T cells and drives their exhaustion. In this context, targeting both tumor and T cell metabolism can beneficially enhance or temper immunity in an inhospitable microenvironment and markedly improve the success of immunotherapies.
... Two approaches have been selected in respect to the potential clinical applications of CTLA-4 in immunotherapy, anti CTLA-4 antibody and CTLA4-Ig, respectively 7,11 . CTLA4-Ig is a fusion protein containing the extracellular domain of CTLA-4 and the Fc portion of human IgG1. ...
Background:
CTLA-4 inhibitory signals prevent cell cycle progression and IL-2 production, leading to a halt on an ongoing immune response. CTLA4-Ig fusion proteins contain the extracellular domain of CTLA-4 and Fc fragment of human IgG antibody. In this study we aimed to fuse the ctla-4 gene encoding the extracellular domain of CTLA-4 molecule with igg1 gene encoding Fc region of human IgG.
Methods:
After primer design, PCR reaction was performed using pfu polymerase enzyme and specific primers. PCR amplified fragment was ligated into the vector containing the human igg1 gene. The resulting fusion fragment of ctla-4 and human igg1 genes was ligated to pBudCE4.1 expression vector.
Results:
Extracellular domain of ctla-4 gene was ligated to igg1 gene and then ctla4-ig fragment was cloned into pBudCE4.1 vector. Construction of the expression vector was confirmed by restriction pattern analysis and sequencing.
Conclusion:
By confirming the construct, in the next step, the recombinant DNA will be used to produce CTLA4-Ig recombinant protein for the clinical uses.
... While the blockade of CTLA-4 signaling using an anti-CTLA-4 Ab resulted in protection against tumors and viral and bacterial infections, the blockade of CD28 signaling using CTLA-4-Ig has shown promise in treating autoimmunity and transplant rejection (9,10,12,13). Although a role for CTLA-4 in the negative regulation of T cells is well recognized, its contribution to Treg function remains controversial (14 -17). ...
... Por lo que al bloquear la función del CTLA-4, se aumenta y prolonga la respuesta inmune de las células T (Figura 4). En estudios fase I, el anticuerpo humano especifico para CTLA-4, sea solo o en combinaciones, ha demostrado respuestas objetivas en pacientes con cáncer de próstata hormona refractario [36][37][38][39] . Otros estudios están actualmente en proceso, los cuales al parecer son promisorios. ...
... immunotherapeutic approach to treat patients with several advanced malignancies, including pancreatic cancer. [16][17][18][19] Taken together, these evidences indicate that CTLA-4 may be a key molecule in oncogenesis of pancreatic cells. ...
Antitumor T lymphocytes play an essential part in immune surveillance of cancer cells. Cytotoxic T lymphocyte-associated Protein 4 (CTLA-4) is a negative regulator of T cell activation and proliferation and therefore influences immune surveillance of carcinogenesis of pancreas. Thus, this study examined the association between functional CTLA-4 49G-to-A (49G>A) single-nucleotide polymorphism and pancreatic cancer risk.
Genotypes were determined in 368 patients with pancreatic cancer and 926 controls, and odds ratios (ORs) and 95% confidence intervals (CIs) were estimated by logistic regression.
A significant increased risk of pancreatic cancer was found to be associated with the CTLA-4 49G>A single-nucleotide polymorphism. Compared with noncarriers, the OR of developing pancreatic cancer for CTLA-4 49 GA or AA carriers was 1.75 (95% CI = 1.34-2.30, P = 4.83 × 10(-5) ) or 2.54 (95% CI = 1.67-3.87, P = 1.36 × 10(-5) ), respectively. In stratified analyses, the association was more pronounced in GA and AA carriers aged ≤60 years (OR = 3.10, 95% CI = 2.15-4.47, P(interaction) = .002), smokers with GA and AA genotypes (OR = 3.92, 95% CI = 2.39-6.43, P(interaction) = .037), and drinkers with GA and AA genotypes (OR = 4.55, 95% CI = 2.65-7.82, P(interaction) = .042), compared with GG carriers. Moreover, a supermultiplicative interaction between the CTLA-4 49AA genotype and smoking plus drinking was also evident in intensifying risk of pancreatic cancer (P(interaction) = 5.64 × 10(-12) ).
These results suggest that CTLA-4 49G>A polymorphism is involved in susceptibility to developing pancreatic cancer, alone and in a gene-environment interaction manner. Cancer 2012. © 2012 American Cancer Society.
... A more recent study has shown a similar benefit in patients with previously untreated metastatic melanoma [14]. Clinical trials have also been conducted in patients with prostate cancer, including studies with ipilimumab alone or in combination with vaccines or GM-CSF, all demonstrating some evidence of efficacy [15][16][17]. At the time of this writing, a randomized, double-blind, phase III trial is currently underway evaluating ipilimumab versus placebo in patients with early metastatic, castrate-resistant prostate cancer (NCT01057810). ...
CTLA-4 blockade has demonstrated antitumor efficacy in human clinical trials. The antitumor mechanism is presumably mediated in part by the expansion of tumor-specific T cells. Androgen deprivation, the cornerstone of treatment for patients with metastatic prostate cancer, has been shown to elicit prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with androgen deprivation, followed by an anti-CTLA-4 antibody, could augment a tumor-specific immune response elicited by androgen deprivation. We report here the results of a phase I trial evaluating a humanized monoclonal antibody targeting CTLA-4, CP-675,206 (tremelimumab), in combination with androgen deprivation using an antiandrogen. Eligible patients were those with PSA-recurrent prostate cancer after primary surgery and/or radiation therapy, not previously treated with androgen deprivation, and without radiographic evidence of metastatic disease. Subjects were treated in two cycles, 3 months apart, in which they received bicalutamide 150 mg daily days 1-28 and tremelimumab on day 29. The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose. Eleven patients were enrolled and completed at least 1 year of follow-up. Dose-limiting toxicities included grade 3 diarrhea and skin rash. No favorable changes in PSA doubling time were observed in a period shortly after completing treatment; however, three patients experienced a prolongation in PSA doubling time detectable several months after completing treatment. The identification of delayed, prolonged favorable changes in serum PSA suggests that future studies could explore this combination in studies evaluating time to disease progression.
... Indeed, several phase I/II trials using humanized monoclonal antibodies (mAbs) to block CTLA-4 signaling have shown promising results in different human cancers [9][10][11][12]. These studies provide evidence that treatment with anti-CTLA-4 mAbs is generally well tolerated and capable of inducing objective tumor responses in patients with prostate cancer, renal cell carcinoma, melanoma, and lymphoma [13][14][15][16][17]. ...
B7-H3 is one of the most recently identified members of the B7/CD28 superfamily of costimulatory molecules serving as an accessory modulator of T-cell response. Recently, B7-H3 expression has been reported in several human cancers indicating an additional function of B7-H3 as a regulator of antitumor immunity. However, its precise physiologic role is still elusive, because both stimulatory and inhibitory capacities have been demonstrated. This paper summarizes the available data on B7-H3 in the regulation of T-cell response focusing on its potential role in antitumor immunity.
... A major target molecule that is expressed by both T Regs and activated T Eff cells is CTLA-4, a CD28 family member that has a 50-100-fold higher affinity for CD80 and CD86 (B7-1, B7-2) than CD28 [25]. CTLA-4 acts as a negative signal by binding B7 molecules on APCs and impairing T cell effector cell expansion through inhibition of IL-2 production, induction of TGF-, initiation of cell-cycle arrest, prevention of stimulatory CD28-B7 interactions [26], and induction of Foxo3 mediated inhibition of IL-6 production [27]. The significance of CTLA-4-B7 interactions in maintaining T cell homeostasis is underscored by the severe autoimmunity and lymphoproliferative disorder observed in CTLA-4 −/− mice [28], making it an attractive target to boost the immunogenicity of cancer vaccines. ...
Abnormal expression of "self" antigens on tumors compared with normal cells provides opportunities and challenges for development of cancer vaccines. We review recent work in pre-clinical transgenic mouse models and in clinical trials that has elucidated multiple regulatory mechanisms that interfere with the induction of effective immunity. We discuss these as being either part of the normal function of the immune system or being driven by the tumor microenvironment. Collectively this work shows that it is possible to design vaccines based on tumor-associated antigens and elicit effective immunity against abnormal expression of these antigens on tumors without causing autoimmunity.
... Variable results have been reported in all trials: metastatic melanoma (often in combination with vaccination and other immunotherapies) have shown an objective response in as high as 22%, complete response rates as high as 8.3% and stable disease in up to 84%. At the other extreme is the relatively poor response seen in cancer of the colon or rectum, with only a single partial response and progressive disease in 46/47 [10][11][12][13][14][15][16][17][18][19][20][21]. ...
Anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) therapies represent a novel approach to cancer treatment via disruption of immune tolerance to antigens located on tumor cells. Disruption of immune tolerance, however, may occur at a cost. A host of immune related adverse events (IRAEs) are associated with anti-CTLA-4 therapy. Autoimmune hypophysitis has been reported in up to 17% of patients with melanoma and renal cell carcinoma treated with this therapy. Familiarity with the spectrum of IRAEs connected to these therapies is paramount for endocrinologists, oncologists and those involved in the care of these subjects. We review here key aspects of diagnosis and treatment of anti-CTLA-4 antibody therapy resultant IRAEs. We describe the first two cases of hypopituitarism in prostate cancer subjects undergoing experimental therapy with ipilimumab. The clinical evidence strongly suggests that the prostate cancer subjects developed autoimmune hypophysitis as a consequence of anti-CTLA-4 treatment. High dose glucocorticoid treatment resulted in markedly improved symptoms, and resolution of focal symptoms and diabetes insipidus. One subject recovered pituitary-thyroid axis function after 9 months; however, both continue to require GC replacement. These cases highlight the importance of early screening and treatment for hypopituitarism in all subjects undergoing treatment with anti-CTLA-4 therapy to prevent a potentially fatal outcome from secondary adrenal insufficiency, a readily treatable disease. We recommend mandatory long term follow-up to monitor the development of other hormonal deficits.
... Many types of solid malignancies, including breast, prostate and brain tumors have well characterized mechanisms of immunosuppression. Local and systemic inhibition of T cell activity can be due in part to factors secreted into the local milieu 9,10 or surface expression of proteins that prevent activation 11 or induce apoptosis 12 of effector cells. In some cases, immunoresistance is correlated with oncogenic pathway activation 13 . ...
Inhibition of the phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) pathway is an appealing method for decreasing the immunoresistance and augmenting T cell-mediated immunotherapy. A major impediment to this strategy is the impact of conventional PI3K/mTOR pathway inhibitors on T cell function. In particular, rapamycin, is a well-known immunosuppressant that can decrease the activity of the PI3K/mTOR pathway in tumor cells, but also has a profound inhibitory effect on T cells. Here we show that Honokiol, a natural dietary product isolated from an extract of seed cones from Magnolia grandiflora, can decrease PI3K/mTOR pathway-mediated immunoresistance of glioma, breast and prostate cancer cell lines, without affecting critical proinflammatory T cell functions. Specifically, we show that at doses sufficient to down-regulate levels of phospho-S6 and the negative immune regulator B7-H1 in tumor cells, Honokiol does not significantly impair T cell proliferation or proinflammatory cytokine production. In contrast to classic inhibitors, including LY294002, wortmannin, AKT inhibitor III and rapamycin, Honokiol specifically decreases the PI3K/mTOR pathway activity in tumor cells, but not in freshly stimulated T cells. Collectively, our data define a unique application for Honokiol and provide the impetus to more fully elucidate the mechanism by which T cells are resistant to the effects of this particular inhibitor. Honokiol is clinically available for human testing and may serve to augment T cell-mediated cancer immunotherapy.
... The immunoregulation of the effector function, migratory and homing properties, as well as the short-or long-term survival of naive (CCR7 + ) and mature or memory T cells, including the polarized Th1 (chemokine CC motif receptor [CCR5] + and C-X-C chemokine receptor [CXCR]3 + ), Th2 (CCR3 + , CCR4 + and CCR8 + ) cells in the effector memory (tissues) and central memory (lymph nodes) compartments of the immune system [61,62]. For example, targeted intermittent or periodic blockade of immune dampening molecules, such as program death-1 ligand and CTLA-4, on T cells may improve long-term memory, as recently suggested from studies involving CTLA-4 [63,64]. ...
... Cytotoxic T lymphocyte-associated protein 4 (CTLA-4) is expressed on activated T cells and competes with CD28 for binding to B7 costimulatory molecules on APCs thereby preventing costimulation and promoting down-regulation of T-cell activity. Treatment with anti-CTLA-4 mAbs alone or in combination with other immunotherapies has been demonstrated to facilitate antitumor immunity and tumor regression in mouse models and clinical trials in PCa [138]. Recently, Small et al [139] performed a clinical trial to determine the efficacy of the humanized mAb ipilimumab in 14 HRPC patients. ...
The absence of effective therapies for advanced prostate cancer has entailed an intensive search for novel treatments. This review presents an overview of specific immunotherapeutic strategies for prostate cancer.
Current literature was reviewed regarding the identification of tumor antigens and the design of T-cell- and antibody-based immunotherapy for prostate cancer. The PubMed database was searched using the key words antibodies, clinical trials, dendritic cells, immunotherapy, prostate cancer, and T cells.
T cells and antibodies are powerful components of the specific antitumor immune response. CD8+ cytotoxic T lymphocytes (CTLs) efficiently destroy tumor cells. CD4+ T cells improve the antigen-presenting capacity of dendritic cells (DCs) and support the stimulation of tumor-reactive CTLs. Monoclonal antibodies exhibit their antitumor effects via antibody-dependent cellular cytotoxicity and complement activation. Consequently, much attention has been given to the identification of tumor antigens that represent attractive targets for specific immunotherapy. Several prostate cancer-related antigens were described and used in clinical trials. Such studies were based on the administration of peptides, proteins, or DNA. Furthermore, men with prostate cancer were vaccinated with peptide-, protein-, or RNA-loaded DCs, which display an extraordinary capacity to induce tumor-reactive T cells. Monoclonal antibodies directed against surface antigens were also used. Clinical trials revealed that immunotherapeutic strategies represent safe and feasible concepts for the induction of immunologic and clinical responses in men with prostate cancer.
Specific immunotherapy represents a promising treatment modality for prostate cancer. Further improvement of the current approaches is required and may be achieved by combining T-cell- and antibody-based vaccination strategies with radio-, hormone-, chemo-, or antiangiogenic therapy.
... Preclinical experiments in cynomolgus monkey models demonstrated that ipilimumab could stimulate humoral immune responses to coadministered vaccines (Keler et al. 2003). Clinical data in cancer patients has been reported for both ipilimumab (Phan et al. 2003;Hodi et al. 2003;Ribas et al. 2004;Attia et al. 2005;Blansfield et al. 2005;Maker et al. 2005, 2005bSanderson et al. 2005Beck et al. 2006;Thompson et al. 2006) and CP-675206 (Ribas et al. 2004, 2005, Reuben et al. 2006. Objective and durable antitumor responses were observed for both drugs. ...
Since the 1986 regulatory approval of muromonomab-CD3, a mouse monoclonal antibody (MAb) directed against the T cell CD3epsilon antigen, MAbs have become an increasingly important class of therapeutic compounds in a variety of disease areas ranging from cancer and autoimmune indications to infectious and cardiac diseases. However, the pathway to the present acceptance of therapeutic MAbs within the pharmaceutical industry has not been smooth. A major hurdle for antibody therapeutics has been the inherent immunogenicity of the most readily available MAbs, those derived from rodents. A variety of technologies have been successfully employed to engineer MAbs with reduced immunogenicity. Implementation of these antibody engineering technologies involves in vitro optimization of lead molecules to generate a clinical candidate. An alternative technology, involving the engineering of strains of mice to produce human instead of mouse antibodies, has been emerging and evolving for the past two decades. Now, with the 2006 US regulatory approval of panitumumab, a fully human antibody directed against the epidermal growth factor receptor, transgenic mice expressing human antibody repertoires join chimerization, CDR grafting, and phage display technologies, as a commercially validated antibody drug discovery platform. With dozens of additional transgenic mouse-derived human MAbs now in clinical development, this new drug discovery platform appears to be firmly established within the pharmaceutical industry.
... Immunoregulatory networks in tumors that interfere with anti-tumor cellular immune responses. [103][104][105][106] stressing the need for further research into how to induce anti-tumor immune responses without eliciting strong autoimmune reactions and even autoimmune disease. ...
Tumor cells often evoke specific immune responses that, however, fail to eliminate all the tumor cells. The development of cancer immunotherapies is, therefore, mostly focused on the generation of large numbers of activated anti-tumor effector cells by vaccination or adoptive T cell transfer. These developments are built on an ever-extended list of identified tumor-associated antigens and corresponding T cell epitopes, and a steady flow of reports from proof-of-principle animal model experiments demonstrating cure from disease by immune interventions. However, the promises have not translated into clinical successes for cancer patients. Even where tumor regression or complete responses were achieved there is usually relapse of the disease. Increasing numbers of reports over recent years highlight potential immunosuppressive mechanisms that act in tumors and systemically in cancer patients to block effective anti-tumor immune responses. They account in large parts for the failures of cancer immunotherapy and need to be overcome before progress can be expected. We review here the current state of the research on immunosuppressive networks in human cancer.
... Evidence garnered from many preclinical studies and recent clinical studies indicates that the control of immune inhibitory entities will ultimately have an important function in vaccine-mediated therapies. The monoclonal antibody anti-CTLA-4 is showing much potential (46)(47)(48)(49). Although the exact mechanism by which this agent works with vaccine has never been shown clinically, preclinical studies have clearly demonstrated that anti-CTLA-4 renders higher avidity antigen-specific T cells when employed with vaccines (50). ...
Cancer vaccines constitute a unique therapeutic modality in that they initiate a dynamic process involving the host's immune response. Consequently, (a) repeated doses (vaccinations) over months may be required before patient clinical benefit is observed and (b) there most likely will be a "dynamic balance" between the induction and maintenance of host immune response elements to the vaccinations vs. host/tumor factors that have the potential to diminish those responses. Thus "patient response" in the form of disease stabilization and prolonged survival may be more appropriate to monitor than strictly adhering to "tumor response" in the form of Response Criteria In Solid Tumors (RECIST) criteria. This can be manifested in the form of enhanced patient benefit to subsequent therapies following vaccine therapy. This article will review these phenomena unique to cancer vaccines with emphasis on prostate cancer vaccines as a prototype for vaccine therapy. The unique features of this modality require the consideration of paradigm shifts both in the way cancer vaccine clinical trials are designed and in the way patient benefit is evaluated.
The formidable advances in cancer treatment have led to remarkable improvements in patient’s survival, so that the major concern shifted from primary tumors to metastatic disease. Brain metastases represent a life-threatening condition with a poor prognosis due to the lack of reliable biomarkers that preclude their timely identification and to the scarce therapeutic possibilities considering that the blood-brain barrier limits the access of most of the drugs to the brain and surgical resection is discouraged in cases of multiple metastases. Moreover, brain metastases have been scarcely investigated, which precludes a comprehensive understanding of the determinants and players, as well as of the complex cross-talk and signaling pathways involved. This chapter summarizes the impressive numbers about cancer and brain metastases and the estimates of progression in the years to come. It also gathers together the relevant concepts about the metastatic cascade, focusing in the extravasation step across the microvascular endothelium that leads to the formation of brain metastases. Moreover, it comprehensively explores the brain tumor microenvironment, detailing on the pre-metastatic niches and their relevance for tumor cell development in the target organ. Additionally, the cellular and acellular components, as well as their interplay, activation status, and acquired phenotypes, are addressed. Collectively, by bringing together historical concepts and state-of-the-art knowledge, this chapter shall contribute to a better understanding of the brain metastasization process, essential for the development of novel approaches to improve patients’ life quality and expectancy.
To explore the prognosis of tumor mutation burden (TMB) and underlying relationships with tumor‐infiltrating immune cells in bladder cancer (BLCA). Transcriptome profiles and somatic mutation data from The Cancer Genome Atlas database by the GDC tool. A total of 437 samples were included, consisted of 412 BLCA patients and matched 25 normal samples. Specific mutation information was summarized and illustrated in waterfall plot. Higher TMB levels revealed improved overall survival (OS) and lower tumor recurrence. We found 68 differentially expressed genes in two TMB groups and identified eight independent hub TMB‐related signature. Pathway analysis suggested that differential TMB‐related signature correlated with multiple cancer‐related crosstalk, including cell cycle, DNA replication, cellular senescence, and p53 signaling pathway. Besides, the tumor mutation burden related signature (TMBRS) model based on eight signature possessed well predictive value with area under curve (AUC) = 0.753, and patients with higher TMBRS scores showed worse OS outcomes (p < .001). Moreover, we exhibited the inferred immune cell fractions in box plot and differential abundance of immune cells were shown in the heatmap. The Wilcoxon rank‐sum test suggested that CD8+ T cell (p = .001) and memory activated CD4+ T cell (p = .004) showed higher infiltrating levels in high‐TMB group, while the density of resting mast cells showed lower infiltrating level in high‐TMB group (p = .016). Finally, it is significant to note that CD8+ T cell and memory activated CD4+ T cell subsets not only revealed higher infiltrating abundance in high‐TMB group but correlated with prolonged OS and lower risk of tumor recurrence, respectively. Tumor mutation burden combined with immune infiltrates in bladder urothelial carcinoma.
Introduction- Progress in the understanding of molecular events of carcinogenesis and cancer evolution as well as the identification of tumor antigens has led to the development of different targeted therapeutic approaches, including the use of monoclonal antibodies (mAbs). Prostate cancer (PC) is highly amenable to mAb targeting given the existence of prostate-specific targets and the natural history and localization of metastatic disease.
Areas covered- Several aspects of the PC phenotype, including growth factors, angiogenesis mediators, bone microenvironment signals, and immune evasion pathways, have become areas of ongoing investigation in terms of mAb targeting. These are reviewed. The greatest success so far has been the development of mAbs against prostate-specific tumor antigen (PSMA), which opened an opportunity to improve diagnostic accuracy and simultaneously target metastatic disease.
Expert opinion- As mAb use in PC continues to evolve, more accurate imaging of the extent of disease and more effective mAb therapies (naked or conjugated with drugs, toxins or radioactive molecules) are emerging. In addition, the combination of mAbs with other treatment modalities is expected to further improve responses and overall survival. Identification of validated biomarkers is necessary for better recognition of patient subgroups who will derive the greatest benefit from mAb therapy.
IntroductionSolutions to the Problem of ImmunogenicityGenetically Engineered MiceThe Role of Immunoglobulin Genes in B-Cell DevelopmentHuman Immunoglobulin Transgenic MiceHuman Therapeutic Applications of Transgenic Mouse Derived MAbsSummaryReferences
In United States, prostate cancer is the most common cancer diagnosis (excluding dermatological malignancies) and the second leading cause of cancer related mortality in men [1]. Early stage prostate cancer has an indolent course; however local tumor progression and aggressive metastatic
disease may develop in the long term [2]. Androgen deprivation therapy provides disease control for a substantial period of time; however the vast majority eventually progress [3, 4]. In hormone refractory cases, chemotherapy with docetaxel and prednisone led to a superior survival and quality
of life [5]. This combination remained as the predominant first line of chemotherapeutic option for a significant period of time. Only recently have new advances in chemotherapeutic, anti-androgen and other novel therapeutic options made it into the clinic. Sipuleucel-T in patients with
castration-resistant metastatic prostate cancer demonstrated a reduction in the risk of death [6]. The sipuleucel-T trial results have helped demonstrate a proof of concept of the potential of immunotherapy in prostate cancer but widespread acceptance of its use has been tempered by the time
limited survival advantage of only four months. Therefore, we continue to need novel agents and combination strategies which build on this initial success. Several other inter-related patho-physiological mechanisms like inflammation and genetic/epigenetic modulation are under investigation
in prostate cancer which could have further implications in the development of these new immunotherapeutic preventive and treatment strategies [7, 8]. In this article we will give an overview about the role and link of inflammation, epigenetic modulation and immune modulation in the development
and treatment of prostate cancer. It is imperative that new approaches that further define immune responsiveness and identify which patients are most likely to benefit. With the increasing availability of novel agents, future advances will also lie in innovative combination strategies.
Systemic therapy of advanced prostate and renal cancers has gained several recent additions to the therapeutic armamentarium. Treatment of patients with castration-resistant prostate cancer now includes additional immunotherapy (sipuleucel-T), chemotherapy (cabazitaxel), androgen-signaling inhibitors (abiraterone acetate, enzalutamide), and a radiopharmaceutical (alpharadin), based on extension of patient survival. Similarly, therapy for patients with renal cell carcinoma, a chemoresistant malignancy, has undergone dramatic changes based on an understanding of the role of angiogenesis. Multiple vascular endothelial growth factor inhibitors (sorafenib, sunitinib, pazopanib, axitinib, bevacizumab) and mammalian target of rapamycin inhibitors (temsirolimus, everolimus) have been added to the therapeutic arsenal. Additionally, immunotherapy retains an important treatment role, with a continuing application of high-dose interleukin-2 in select patients and the emergence of novel immunotherapeutic agents that may have significant benefit. Other major urologic malignancies, including urothelial, testicular, and penile cancers, have witnessed relatively few or no recent advances in therapy, although testicular germ cell tumors are one of the most curable malignancies. An agent for treatment of advanced urothelial cancer now has commercial approval, the chemotherapeutic agent, vinflunine, as second-line therapy in multiple countries-but not in the United States. Our review summarizes and updates the field of systemic therapy for advanced urologic malignancies, with a focus on castration-resistant prostate cancer and renal cell carcinoma.
The immune system has demonstrated the ability to participate in cancer surveillance, but its role in promoting anticancer
activity has only begun to be harnessed. Advances over the last 10 years have made the possibility of immunotherapy for the
treatment of cancer a more realistic possibility. Prostate cancer is an ideal target for immunotherapy given its relatively
slow growth rate and the time required to generate immune responses. This chapter will discuss an antibody to cytotoxic T
lymphocyte antigen-4 (CTLA-4), which can dampen the restraints on T-cell activity to incite a T cell response to tumor, resulting
in immune-mediated tumor regression, and the experience with this mechanism in treating advanced prostate cancer.
The field of tumor vaccination is currently undergoing a shift in focus, from individualized tailor-made vaccines to more generally applicable vaccine formulations. Although primarily predicated by financial and logistic considerations, stemming from a growing awareness that clinical development for wide-scale application can only be achieved through backing from major pharmaceutical companies, these new approaches are also supported by a growing knowledge of the intricacies and minutiae of antigen presentation and effector T-cell activation. Here, the development of whole-cell tumor and dendritic cell (DC)-based vaccines from an individualized autologous set-up to a more widely applicable allogeneic approach will be discussed as reflected by translational studies carried out over the past two decades at our laboratories and clinics in the vrije universiteit medical center (VUmc) in Amsterdam, The Netherlands.
Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is an important regulator and functions negatively in immune response. Its nonsynonymous polymorphism +49G > A (dbSNP: rs231775) has been linked to an elevated risk of T-cell-mediated autoimmune diseases, infectious diseases, and even carcinomas. Here, we examined the genotypes at rs231775 of 1003 subjects in a Han Chinese population to detect the association between this single-nucleotide polymorphism (SNP) and hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) susceptibility, including 375 HBV-related HCC patients, 209 non-HCC patients with HBV infection, and 419 healthy controls. Our results indicated a weak trend for the relationship between rs231775 and HBV-related HCC susceptibility, although the statistical level was not significant. However, a significant difference was identified in males between HBV-related HCC patients and healthy controls. The data revealed that the frequency of the A/A genotype was higher in patients compared with healthy controls (odds ratio [OR] = 1.79, 95% confidence interval [95% CI] 1.05-3.08). The G allele appeared to have a protective effect in developing HBV-related HCC. Subjects with the A allele had higher HCC susceptibility than those with the G allele (OR = 1.31, 95% CI 1.03-1.66). These results suggested that the A/A genotype and A allele of rs231775 increased the risk of developing HBV-related HCC in a male Chinese population.
Cryoablation is gaining acceptance as a primary treatment of localized as well as a salvage therapy of metastatic urologic malignancies. Anecdotal clinical reports suggest cryoablation can induce a systemic anti-tumor immune response; this phenomenon has been confirmed in animal models. To capitalize on this stimulatory effect of cryotherapy for control of advanced malignancies, it must be further intensified. This article reviews the existing evidence regarding cryoimmunology and discusses the mechanisms for generation of an anti-tumor immune response. Several immunotherapy approaches that can be combined with cryoablation to devise a cryoimmunotherapeutic strategy with potential to affect the progression of metastatic disease are described.
In this issue, O'Mahony et al. ([1][1]) targeted CTL–associated antigen 4 (CTLA-4) in previously vaccinated solid tumor patients using the human anti–CTLA-4 antibody ipilimumab (MDX-010). Ipilimumab, together with a second human anti–CTLA-4 antibody, ticilimumab, are currently in phase 3
Basic immunology research over several decades has led to an improved understanding of tumor recognition by components of the immune system and mechanisms of tumor evasion from immune detection. These findings have ultimately led to four phase III trials, currently underway, evaluating antitumor active immunotherapies in patients with prostate cancer. This article reviews recent published findings in the area of prostate cancer immunotherapies, focusing on both passive and active immunotherapy approaches that have entered clinical trials.
Clinical trials with immune active agents reported in the last year have demonstrated efficacy in the treatment of prostate cancer. These agents include immune modulators such as granulocyte-macrophage colony stimulating factor and anticytotoxic T-lymphocyte-associated antigen 4 monoclonal antibodies, antibody therapies targeting prostate-specific membrane antigen, and vaccines such as those targeting prostatic acid phosphatase, prostate-specific antigen, and cellular vaccines expressing granulocyte-macrophage colony stimulating factor.
Results from several recent clinical trials have suggested that immune-based therapies have clinical benefit in patients with prostate cancer with potentially less toxicity than traditional systemic treatments. We review recent reports of immunotherapies being evaluated in patients with prostate cancer, and highlight the direction for these therapies in combination with other immunotherapies and other traditional therapies.
The field of cancer vaccines is currently in an active state of preclinical and clinical investigations. Although no therapeutic cancer vaccine has to date been approved by the Food and Drug Administration, several new paradigms are emerging from recent clinical findings both in the use of combination therapy approaches and, perhaps more importantly, in clinical trial design and end point analyses. This article will review recent clinical trials involving several different cancer vaccines from which data are emerging contrasting classic "tumor response" (Response Evaluation Criteria in Solid Tumors) criteria with "patient response" in the manifestation of increased patient survival post-vaccine therapy. Also described are several strategies in which cancer vaccines can be exploited in combination with other agents and therapeutic modalities that are quite unique when compared with "conventional" combination therapies. This is most likely due to the phenomena that (a) cancer vaccines initiate a dynamic immune process that can be exploited in subsequent therapies and (b) both radiation and certain chemotherapeutic agents have been shown to alter the phenotype of tumor cells as to render them more susceptible to T-cell--mediated killing. Consequently, evidence is emerging from several studies in which patient cohorts who first receive a cancer vaccine (as contrasted with control cohorts) benefit clinically from subsequent therapies.
CTLA-4 is a member of the costimulatory family, has homology to CD28, and binds the B7 family of ligands. Unlike CD28, CTLA-4 ligation transmits a negative signal in T cells. CTLA-4 expression, while inducible in most T cells, is expressed constitutively on T cells with a regulatory phenotype. The mechanism controlling CTLA-4 expression in human T cells is poorly characterized, thus we sought to better understand the mechanism of activation of the CTLA-4 gene. By cloning the 5' upstream promoter and creating promoter-deletion reporter constructs, we show that the proximal promoter is critical for activating the CTLA-4 gene. Within this region, we identify a NFAT consensus sequence that binds NFAT with high affinity that differs from other NFAT sequences and does not recruit AP-1. Analysis of the chromatin proteins in the native CTLA-4 gene shows that this promoter region becomes associated with acetylated histones by chromatin immunoprecipitation assays. In addition, NFAT1 binds to the promoter of the CTLA-4 gene after stimulation by chromatin immunoprecipitation. The functional requirement of the NFAT site for CTLA-4 transcription was demonstrated by mutations in the NFAT site that abolished the activity of the promoter. Furthermore, inhibitors of NFAT suppressed CTLA-4 gene expression, indicating that NFAT plays a critical role in regulating the induction of the CTLA-4 gene in lymphocytes. The identification of NFAT as a critical regulator of the CTLA-4 gene suggests that targeting NFAT function may lead to novel approaches to modulate the CTLA-4 gene to control the immune response.
CTLA-4 is a critical negative regulator of T cell response and is instrumental in maintaining immunological tolerance. In this article, we report that enhanced selective engagement of CTLA-4 on T cells by Ag-presenting dendritic cells resulted in the induction of Ag-specific CD4(+)CD25(+)Foxp3(+) and CD4(+)CD25(-)TGF-beta1(+) adaptive Tregs. These cells were CD62L(low) and hyporesponsive to stimulation with cognate Ag but demonstrated a superior ability to suppress Ag-specific effector T cell response compared with their CD62L(high) counterparts. Importantly, treatment of mice with autoimmune thyroiditis using mouse thyroglobulin (mTg)-pulsed anti-CTLA-4 agonistic Ab-coated DCs, which results in a dominant engagement of CTLA-4 upon self-Ag presentation, not only suppressed thyroiditis but also prevented reemergence of the disease upon rechallenge with mTg. Further, the disease suppression was associated with significantly reduced mTg-specific T cell and Ab responses. Collectively, our results showed an important role for selective CTLA-4 signaling in the induction of adaptive Tregs and suggested that approaches that allow dominant CTLA-4 engagement concomitant with Ag-specific TCR ligation can be used for targeted therapy.
This review provides a review of the basic biology of the major cytokines under consideration for use in tumor immunotherapy. The authors also describe the clinical role of cytokine therapy for human tumors, with a focus on melanoma and renal cell carcinoma. Finally, they present details of new cytokines and suggest possible direction for future clinical investigation using new cytokines or combinations of biologic agents. A better understanding of cytokine biology, coupled with new insights into the role of immunoregulation and the microenvironment in patients who have cancer, has provided new therapeutic targets for the treatment of human cancer.
Despite improvement in conventional strategies for treating gastrointestinal (GI) carcinoma, large numbers of patients still suffer from incurable or progressive disease.
Here we consider the prospects for circumventing limitations and maximising the efficacy of different immunotherapies.
We summarise different cancer vaccines and targeted drugs and highlight the scientific rationale of using immunotherapy for targeting GI cancers, in addition to the potential strategies for improving immunotherapeutic efficacy.
Many cancer vaccines and antibody-directed therapies have been tested in early phase clinical trials and demonstrated proof of concept and safety. As yet few have been properly evaluated for clinical efficacy; although adoptive transfer of tumour-associated-antigen-specific T cells has shown dramatic clinical responses in some patients. The recognition of a role for T regulatory cells in limiting anti-tumour immunity has provided momentum for developing strategies to over-ride such immunoinhibitory effects. There is some evidence that conventional therapies may work by influencing these negative factors and allowing expression of immune control mechanisms. An important developing area for clinical evaluation is the testing of combined conventional and immunotherapeutic modalities which may provide for synergy; thereby circumventing the limitations of individualised treatments and generating additional clinical benefits.
This report shows that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) plays a key role in T cell-mediated dominant immunologic self-tolerance. In vivo blockade of CTLA-4 for a limited period in normal mice leads to spontaneous development of chronic organ-specific au- toimmune diseases, which are immunopathologically similar to human counterparts. In normal naive mice, CTLA-4 is constitutively expressed on CD25 1 CD4 1 T cells, which constitute 5-10% of peripheral CD4 1 T cells. When the CD25 1 CD4 1 T cells are stimulated via the T cell re- ceptor in vitro, they potently suppress antigen-specific and polyclonal activation and prolifera- tion of other T cells, including CTLA-4-deficient T cells, and blockade of CTLA-4 abrogates the suppression. CD28-deficient CD25 1 CD4 1 T cells can also suppress normal T cells, indi- cating that CD28 is dispensable for activation of the regulatory T cells. Thus, the CD25 1 CD4 1 regulatory T cell population engaged in dominant self-tolerance may require CTLA-4 but not CD28 as a costimulatory molecule for its functional activation. Furthermore, interference with this role of CTLA-4 suffices to elicit autoimmune disease in otherwise normal animals, pre- sumably through affecting CD25 1 CD4 1 T cell-mediated control of self-reactive T cells. This unique function of CTLA-4 could be exploited to potentiate T cell-mediated immunoregula- tion, and thereby to induce immunologic tolerance or to control autoimmunity.
CD28/B7 costimulation has been implicated in the induction and progression of autoimmune diseases. Experimentally induced models of autoimmunity have been shown to be prevented or reduced in intensity in mice rendered deficient for CD28 costimulation. In sharp contrast, spontaneous diabetes is exacerbated in both B7-1/B7-2-deficient and CD28-deficient NOD mice. These mice present a profound decrease of the immunoregulatory CD4+CD25+ T cells, which control diabetes in prediabetic NOD mice. These cells are absent from both CD28KO and B7-1/B7-2KO mice, and the transfer of this regulatory T cell subset from control NOD animals into CD28-deficient animals can delay/prevent diabetes. The results suggest that the CD28/ B7 costimulatory pathway is essential for the development and homeostasis of regulatory T cells that control spontaneous autoimmune diseases.
Cancer relapse after surgery is a common occurrence, most frequently resulting from the outgrowth of minimal residual disease in the form of metastases. We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade as an adjunctive immunotherapy to reduce metastatic relapse after primary prostate tumor resection. For these studies, we developed a murine model in which overt metastatic outgrowth of TRAMP-C2 (C2) prostate cancer ensues after complete primary tumor resection. Metastatic relapse in this model occurs reliably and principally within the draining lymph nodes in close proximity to the primary tumor, arising from established metastases present at the time of surgery. Using this model, we demonstrate that adjunctive CTLA-4 blockade administered immediately after primary tumor resection reduces metastatic relapse from 97.4 to 44%. Consistent with this, lymph nodes obtained 2 weeks after treatment reveal marked destruction or complete elimination of C2 metastases in 60% of mice receiving adjunctive anti-CTLA-4 whereas 100% of control antibody-treated mice demonstrate progressive C2 lymph node replacement. Our study demonstrates the potential of adjunctive CTLA-4 blockade immunotherapy to reduce cancer relapse emanating from minimal residual metastatic disease and may have broader implications for improving the capability of immunotherapy by combining such forms of therapy with other cytoreductive measures including surgery.
While interactions between CD28 and members of the B7 family costimulate and enhance T cell responses, recent evidence indicates that the CD28 homologue CTLA-4 plays a downregulatory role. The mechanism by which this occurs is not clear, but it has been suggested that CTLA-4 terminates ongoing responses of activated T cells, perhaps by induction of apoptosis. Here we demonstrate that CTLA-4 engagement by antibody cross-linking or binding to B7 inhibits proliferation and accumulation of the primary T cell growth factor, IL-2, by cells stimulated with anti-CD3 and anti-CD28. This inhibition is not a result of enhanced cell death. Rather it appears to result from restriction of transition from the G1 to the S phase of the cell cycle. Our observation that upregulation of both the IL-2R alpha chain and the CD69 activation antigen are inhibited by CTLA-4 engagement supplies further evidence that CTLA-4 restricts the progression of T cells to an activated state. Together this data demonstrates that CTLA-4 can regulate T cell activation in the absence of induction of apoptotic cell death.
The identification of potentially useful immune-based treatments for prostate cancer has been severely constrained by the
scarcity of relevant animal research models for this disease. Moreover, some of the most critical mechanisms involved in complete
and proper antitumoral T cell activation have only recently been identified for experimental manipulation, namely, components
involved in the costimulatory pathway for T cell activation. Thus, we have established a novel syngeneic murine prostate cancer
model that permits us to examine two distinct manipulations intended to elicit an antiprostate cancer response through enhanced
T cell costimulation: (i) provision of direct costimulation by prostate cancer cells transduced to express the B7.1 ligand and (ii) in vivo antibody-mediated blockade of the T cell CTLA-4, which prevents T cell down-regulation. In the present study we found that
a tumorigenic prostate cancer cell line, TRAMPC1 (pTC1), derived from transgenic mice, is rejected by syngeneic C57BL/6 mice,
but not athymic mice, after this cell line is transduced to express the costimulatory ligand B7.1. Also, we demonstrated that
in vivo antibody-mediated blockade of CTLA-4 enhances antiprostate cancer immune responses. The response raised by anti-CTLA-4 administration
ranges from marked reductions in wild-type pTC1 growth to complete rejection of these cells. Collectively, these experiments
suggest that appropriate manipulation of T cell costimulatory and inhibitory signals may provide a fundamental and highly
adaptable basis for prostate cancer immunotherapy. Additionally, the syngeneic murine model that we introduce provides a comprehensive
system for further testing of immune-based treatments for prostate cancer.
Cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), a second counterreceptor for the B7 family of costimulatory molecules, functions as a negative regulator of T-cell activation. Here, we investigated whether the blockade of the CTLA-4 function leads to enhancement of antitumor T-cell responses at various stages of tumor growth. Unfractionated spleen cells taken from CSAIM fibrosarcoma-bearing mice 1-2 weeks after CSA1M cell implantation (early tumor-bearing mice) contained tumor-primed T cells that produced interleukin 2 and IFN-gamma through collaboration with antigen-presenting cell-binding tumor antigens when cultured in vitro. However, this initial lymphokine-producing capacity decreased at later stages of tumor growth (7-10 weeks after tumor cell implantation). Anti-CTLA-4 monoclonal antibody (mAb) was added to whole-spleen cell cultures from early or late tumor-bearing mice. Spleen cells from early tumor-bearing mice exhibited enhanced production of interleukin 2 and IFN-gamma upon in vitro culture in the presence of anti-CTLA-4 mAb. However, addition of anti-CTLA-4 mAb to whole-spleen cell cultures from late tumor-bearing mice failed to display such an enhancement. Consistent with these in vitro results, the in vivo antitumor effect of anti-CTLA-4 administration was observed in a tumor-bearing stage-restricted manner; in vivo administration of anti-CTLA-4 (1 mg/mouse, three times at 1-week intervals) into early tumor-bearing mice resulted in regression of growing tumors, whereas the same treatment did not affect tumor growth when performed for late tumor-bearing mice. Similar anti-CTLA-4 effect was observed in another tumor (OV-HM ovarian carcinoma) model. These in vitro and in vivo results indicate that CTLA-4 blockade in tumor-bearing individuals enhances the capacity to generate antitumor T-cell responses, but the expression of such an enhancing effect is restricted to early stages of tumor growth.
Evidence has been accumulating that shows that insulin-dependent diabetes is subject to immunoregulation. To determine whether cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is involved, we injected anti-CTLA-4 mAb into a TCR transgenic model of diabetes at different stages of disease. When injected into young mice, months before they would normally become diabetic, anti-CTLA-4 induced diabetes rapidly and essentially universally; this was not the result of a global activation of T lymphocytes, but did reflect a much more aggressive T cell infiltrate in the pancreatic islets. These effects were only observed if anti-CTLA-4 was injected during a narrow time window, before the initiation of insulitis. Thus, engagement of CTLA-4 at the time when potentially diabetogenic T cells are first activated is a pivotal event; if engagement is permitted, invasion of the islets occurs, but remains quite innocuous for months, if not, insulitis is much more aggressive, and diabetes quickly ensues.
Evidence indicates that cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) may negatively regulate T cell activation, but the basis for the inhibitory effect remains unknown. We report here that cross-linking of CTLA-4 induces transforming growth factor beta (TGF-beta) production by murine CD4(+) T cells. CD4(+) T helper type 1 (Th1), Th2, and Th0 clones all secrete TGF-beta after antibody cross-linking of CTLA-4, indicating that induction of TGF-beta by CTLA-4 signaling represents a ubiquitous feature of murine CD4(+) T cells. Stimulation of the CD3-T cell antigen receptor complex does not independently induce TGF-beta, but is required for optimal CTLA-4-mediated TGF-beta production. The consequences of cross-linking of CTLA-4, together with CD3 and CD28, include inhibition of T cell proliferation and interleukin (IL)-2 secretion, as well as suppression of both interferon gamma (Th1) and IL-4 (Th2). Moreover, addition of anti-TGF-beta partially reverses this T cell suppression. When CTLA-4 was cross-linked in T cell populations from TGF-beta1 gene-deleted (TGF-beta1(-/-)) mice, the T cell responses were only suppressed 38% compared with 95% in wild-type mice. Our data demonstrate that engagement of CTLA-4 leads to CD4(+) T cell production of TGF-beta, which, in part, contributes to the downregulation of T cell activation. CTLA-4, through TGF-beta, may serve as a counterbalance for CD28 costimulation of IL-2 and CD4(+) T cell activation.
The costimulatory molecules B7-1 and B7-2 regulate T lymphocyte activation by delivering activating signals through CD28 and inhibitory signals through cytotoxic T lymphocyte-associated antigen 4 (CTLA-4). The importance of CTLA-4-mediated inhibition was demonstrated by the uncontrolled T cell activation and lymphoproliferative disease that develops in CTLA-4-deficient (-/-) mice. To examine the role of B7 signaling in the activation of CTLA-4-deficient T cells, we bred CTLA-4(-/-) mice with mice lacking B7-1, B7-2, or both B7 molecules. The CTLA-4/B7-1(-/-) and the CTLA-4/B7-2(-/-) mice develop lymphoproliferation and enhanced T cell activation. Mice lacking CTLA-4, B7-1, and B7-2 have a normal life-span, and do not have lymphocytic infiltrates in any organs, or increased T cell activation. Therefore, the two B7 molecules have overlapping functions, since either B7-1 or B7-2 alone can cause the CTLA-4(-/-) phenotype. Elimination of both B7-1 and B7-2 from the CTLA-4- deficient mouse abrogates the lymphocyte activation and disease, and does not reveal evidence for additional stimulatory CD28 ligands. The CTLA-4(-/-) phenotype can be reproduced with anti-CD28 antibody in mice lacking CTLA-4, B7-1, and B7-2, but wild-type mice are unaffected by the same treatment. This suggests that the inhibitory function of CTLA-4 can overcome strong CD28-mediated signaling in vivo.
CTLA-4 engagement by mAbs inhibits, while CD28 enhances, IL-2 production and proliferation upon T cell activation. Here, we have analyzed the mechanisms involved in CTLA-4-mediated inhibition of T cell activation of naive CD4+ T cells using Ab cross-linking. CTLA-4 ligation inhibited CD3/CD28-induced IL-2 mRNA accumulation by inhibiting IL-2 transcription, which appears to be mediated in part through decreasing NF-AT accumulation in the nuclei. However, CTLA-4 ligation did not appear to affect the CD28-mediated stabilization of IL-2 mRNA. Further, CTLA-4 engagement inhibited progression through the cell cycle by inhibiting the production of cyclin D3, cyclin-dependent kinase (cdk)4, and cdk6 when the T cells were stimulated with anti-CD3/CD28 and with anti-CD3 alone. These results indicate that CTLA-4 signaling inhibits events early in T cell activation both at IL-2 transcription and at the level of IL-2-independent events of the cell cycle, and does not simply oppose CD28-mediated costimulation.
We examined the effectiveness of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) blockade, alone or in combination with a granulocyte/macrophage colony-stimulating factor (GM-CSF)-expressing tumor cell vaccine, on rejection of the highly tumorigenic, poorly immunogenic murine melanoma B16-BL6. Recently established tumors could be eradicated in 80% (68/85) of the cases using combination treatment, whereas each treatment by itself showed little or no effect. Tumor rejection was dependent on CD8(+) and NK1.1(+) cells but occurred irrespective of the presence of CD4(+) T cells. Mice surviving a primary challenge rejected a secondary challenge with B16-BL6 or the parental B16-F0 line. The same treatment regimen was found to be therapeutically effective against outgrowth of preestablished B16-F10 lung metastases, inducing long-term survival. Of all mice surviving B16-BL6 or B16-F10 tumors after combination treatment, 56% (38/68) developed depigmentation, starting at the site of vaccination or challenge and in most cases progressing to distant locations. Depigmentation was found to occur in CD4-depleted mice, strongly suggesting that the effect was mediated by CTLs. This study shows that CTLA-4 blockade provides a powerful tool to enhance T cell activation and memory against a poorly immunogenic spontaneous murine tumor and that this may involve recruitment of autoreactive T cells.
The OX-40 receptor (OX-40R), a member of the TNFR family, is primarily expressed on activated CD4+ T lymphocytes. Engagement of the OX-40R, with either OX-40 ligand (OX-40L) or an Ab agonist, delivers a strong costimulatory signal to effector T cells. OX-40R+ T cells isolated from inflammatory lesions in the CNS of animals with experimental autoimmune encephalomyelitis are the cells that respond to autoantigen (myelin basic protein) in vivo. We identified OX-40R+ T cells within primary tumors and tumor-invaded lymph nodes of patients with cancer and hypothesized that they are the tumor-Ag-specific T cells. Therefore, we investigated whether engagement of the OX-40R in vivo during tumor priming would enhance a tumor-specific T cell response. Injection of OX-40L:Ig or anti-OX-40R in vivo during tumor priming resulted in a significant improvement in the percentage of tumor-free survivors (20-55%) in four different murine tumors derived from four separate tissues. This anti-OX-40R effect was dose dependent and accentuated tumor-specific T cell memory. The data suggest that engagement of the OX-40R in vivo augments tumor-specific priming by stimulating/expanding the natural repertoire of the host's tumor-specific CD4+ T cells. The identification of OX-40R+ T cells clustered around human tumor cells in vivo suggests that engagement of the OX-40R may be a practical approach for expanding tumor-reactive T cells and thereby a method to improve tumor immunotherapy in patients with cancer.
It is now clear that functionally specialized regulatory T (Treg) cells exist as part of the normal immune repertoire, preventing the development of pathogenic responses to both self- and intestinal antigens. Here, we report that the Treg cells that control intestinal inflammation express the same phenotype (CD25(+)CD45RB(low)CD4(+)) as those that control autoimmunity. Previous studies have failed to identify how CD25(+) Treg cells function in vivo. Our studies reveal that the immune-suppressive function of these cells in vivo is dependent on signaling via the negative regulator of T cell activation cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), as well as secretion of the immune-suppressive cytokine transforming growth factor beta. Strikingly, constitutive expression of CTLA-4 among CD4(+) cells was restricted primarily to Treg cells, suggesting that CTLA-4 expression by these cells is involved in their immune-suppressive function. These findings raise the possibility that Treg cell function contributes to the immune suppression characteristic of CTLA-4 signaling. Identification of costimulatory molecules involved in the function of Treg cells may facilitate further characterization of these cells and development of new therapeutic strategies for the treatment of inflammatory diseases.
Manipulations capable of breaking host tolerance to induce tissue-specific T cell-mediated inflammation are of central importance to tumor immunotherapy and our understanding of autoimmunity. We demonstrate that androgen ablative therapy induces profuse T cell infiltration of benign glands and tumors in human prostates. T cell infiltration is readily apparent after 7-28 days of therapy and is comprised predominantly of a response by CD4+ T cells and comparatively fewer CD8+ T cells. Also, T cells within the treated prostate exhibit restricted TCR Vbeta gene usage, consistent with a local oligoclonal response. Recruitment/activation of antigen-presenting cells in treated prostate tissues may contribute to local T cell activation. The induction of T cell infiltration in prostate tissues treated with androgen ablation may have implications for the immunotherapeutic treatment of prostate cancer as well as other hormone-sensitive malignancies, including breast carcinoma.
Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that, expressed by different cell types, has regulatory effects on T cells resulting from tryptophan depletion in specific local tissue microenvironments. Different mechanisms, however, might contribute to IDO-dependent immune regulation. We show here that tryptophan metabolites in the kynurenine pathway, such as 3-hydroxyanthranilic and quinolinic acids, will induce the selective apoptosis in vitro of murine thymocytes and of Th1 but not Th2 cells. T cell apoptosis was observed at relatively low concentrations of kynurenines, did not require Fas/Fas ligand interactions, and was associated with the activation of caspase-8 and the release of cytochrome c from mitochondria. When administered in vivo, the two kynurenines caused depletion of specific thymocyte subsets in a fashion qualitatively similar to dexamethasone. These data suggest that the selective deletion of T lymphocytes may be a major mechanism whereby tryptophan metabolism affects immunity under physiopathologic conditions.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) plays a critical role in peripheral tolerance. However, regulatory pathways initiated by the interactions of CTLA-4 with B7 counterligands expressed on antigen-presenting cells are not completely understood. We show here that long-term survival of pancreatic islet allografts induced by the soluble fusion protein CTLA-4-immunoglobulin (CTLA-4-Ig) is contingent upon effective tryptophan catabolism in the host. In vitro, we show that CTLA-4-Ig regulates cytokine-dependent tryptophan catabolism in B7-expressing dendritic cells. These data suggest that modulation of tryptophan catabolism is a means by which CTLA-4 functions in vivo and that CTLA-4 acts as a ligand for B7 receptor molecules that transduce intracellular signals.
A large number of cancer-associated gene products evoke immune recognition, but host reactions rarely impede disease progression. The weak immunogenicity of nascent tumors contributes to this failure in host defense. Therapeutic vaccines that enhance dendritic cell presentation of cancer antigens increase specific cellular and humoral responses, thereby effectuating tumor destruction in some cases. The attenuation of T cell activation by cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) further limits the potency of tumor immunity. In murine systems, the administration of antibodies that block CTLA-4 function inhibits the growth of moderately immunogenic tumors and, in combination with cancer vaccines, increases the rejection of poorly immunogenic tumors, albeit with a loss of tolerance to normal differentiation antigens. To gain a preliminary assessment of the biologic activity of antagonizing CTLA-4 function in humans, we infused a CTLA-4 blocking antibody (MDX-CTLA4) into nine previously immunized advanced cancer patients. MDX-CTLA4 stimulated extensive tumor necrosis with lymphocyte and granulocyte infiltrates in three of three metastatic melanoma patients and the reduction or stabilization of CA-125 levels in two of two metastatic ovarian carcinoma patients previously vaccinated with irradiated, autologous granulocyte-macrophage colony-stimulating factor-secreting tumor cells. MDX-CTLA4 did not elicit tumor necrosis in four of four metastatic melanoma patients previously immunized with defined melanosomal antigens. No serious toxicities directly attributable to the antibody were observed, although five of seven melanoma patients developed T cell reactivity to normal melanocytes. These findings suggest that CTLA-4 antibody blockade increases tumor immunity in some previously vaccinated cancer patients.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is a critical immunoregulatory molecule (expressed on activated T cells and a subset of regulatory T cells) capable of down-regulating T cell activation. Blockade of CTLA-4 has been shown in animal models to improve the effectiveness of cancer immunotherapy. We thus treated 14 patients with metastatic melanoma by using serial i.v. administration of a fully human anti-CTLA-4 antibody (MDX-010) in conjunction with s.c. vaccination with two modified HLA-A*0201-restricted peptides from the gp100 melanoma-associated antigen, gp100:209-217(210M) and gp100:280-288(288V). This blockade of CTLA-4 induced grade III/IV autoimmune manifestations in six patients (43%), including dermatitis, enterocolitis, hepatitis, and hypophysitis, and mediated objective cancer regression in three patients (21%; two complete and one partial responses). This study establishes CTLA-4 as an important molecule regulating tolerance to "self" antigens in humans and suggests a role for CTLA-4 blockade in breaking tolerance to human cancer antigens for cancer immunotherapy.
Regulatory T (T(R)) cells manifest constitutive expression of cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), but the function of CTLA-4 in mediating the regulatory function of T(R) cells is unclear. We show here that mouse CD4+CD25+ cells, either resting or induced to overexpress CTLA-4 by treatment with antibody to CD3, initiated tryptophan catabolism in dendritic cells through a CTLA-4-dependent mechanism. This process required B7 expression and cytokine production by the dendritic cells. In contrast, T(R) cells cultured in the presence of bacterial lipopolysaccharide induced tryptophan catabolism by dendritic cells in a CTLA-4-independent but cytokine-dependent way. Thus, regulation of immunosuppressive tryptophan catabolism in dendritic cells might represent a major mechanism of action of T(R) cells.
The activation of T cells plays a central role in antitumor immunity. In order to activate naïve T cells, two key signals are required. Signal one is provided through the T-cell receptor (TCR) while signal two is that of costimulation. The CD28:B7 molecules are one of the best-studied costimulatory pathways, thought to be the main mechanism through which primary T-cell stimulation occurs. However, a number of molecules have been identified which serve to amplify and diversify the T-cell response, following initial T-cell activation. These include the more recently described 4-1BB:4-1BB ligand (4-1BBL) molecules. 4-1BB:4-1BBL are a member of the TNFR:TNF ligand family, which are expressed on T cells and antigen-presenting cells (APCs), respectively. Therapies utilizing the 4-1BB:4-1BBL signaling pathway have been shown to have antitumor effects in a number of model systems. In this paper, we focus on the 4-1BB:4-1BBL costimulatory molecules. In particular, we will describe the structure and function of the 4-1BB molecule, its receptor and how 4-1BB:4-1BBL costimulation has and may be used for the immunotherapy of cancer.
The immune modulatory molecule CTLA-4 (CD152), through interactions with the B7 costimulatory molecules, has been shown to be a negative regulator of T cell activation in various murine model systems. Abs that block CTLA-4 function can enhance immune responses that mediate potent antitumor activity. However, CTLA-4 blockade can also exacerbate autoimmune disease. The safety and activity of anti-CTLA-4 Abs in primates has not been addressed. To that end, we generated human Abs against CTLA-4 using transgenic mice expressing human Ig genes. A high affinity Ab (10D1) that blocked the binding of CTLA-4 to the B7-1 and B7-2 ligands and had cross-reactivity with macaque CTLA-4 was chosen for further development. Administration of 10D1 to cynomolgus macaques significantly enhanced Ab responses to hepatitis surface Ag and a human melanoma cell vaccine. Anti-self Ab responses as measured by immunoassays using lysate from melanocyte-rich tissues were elicited in those animals receiving the melanoma cell vaccine and anti-CTLA-4 Ab. Remarkably, chronic administration of 10D1 did not result in measurable polyclonal T cell activation, significant alteration of the lymphocyte subsets, or induce clinically observable autoimmunity. Repeated dosing of the 10D1 did not elicit monkey anti-human Ab responses in the monkeys. These observations support the development of CTLA-4 blockade for human immunotherapy.
Etude du controle de la proliferation des lymphocytes T par les cellules presentant l'antigene. Examen des signaux biologiques et biochimiques impliques dans ce mecanisme. Proposition d'un modele permettant d'expliquer les phenomenes
The role of the cell-surface molecule CTLA-4 in the regulation of T cell activation has been controversial. Here, lymph nodes
and spleens of CTLA-4-deficient mice accumulated T cell blasts with up-regulated activation markers. These blast cells also
infiltrated liver, heart, lung, and pancreas tissue, and amounts of serum immunoglobulin were elevated. The mice invariably
became moribund by 3 to 4 weeks of age. Although CTLA-4-deficient T cells proliferated spontaneously and strongly when stimulated
through the T cell receptor, they were sensitive to cell death induced by cross-linking of the Fas receptor and by gamma irradiation.
Thus, CTLA-4 acts as a negative regulator of T cell activation and is vital for the control of lymphocyte homeostasis.
The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation. Signaling through this pathway is complex due to the presence of two B7 family members, B7-1 and B7-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4 in T cell activation. To elucidate the in vivo function of CTLA-4, we generated CTLA-4-deficient mice. These mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3-4 weeks of age. The phenotype of the CTLA-4-deficient mouse strain is supported by studies that have suggested a negative role for CTLA-4 in T cell activation. The severe phenotype of mice lacking CTLA-4 implies a critical role for CTLA-4 in down-regulating T cell activation and maintaining immunologic homeostasis. In the absence of CTLA-4, peripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury.
T cell receptor stimulation without costimulation is insufficient for the induction of an optimal immune response. It is thought
that engagement of the CD28 molecule with its ligand B7 provides an essential costimulatory signal without which full activation
of T cells cannot occur. A mouse strain with a defective CD28 gene was established. Development of T and B cells in the CD28-deficient
mice appeared normal. However, T lymphocytes derived from CD28-/- mutant mice had impaired responses to lectins. Lectin stimulation
did not trigger interleukin-2 (IL-2) production, IL-2 receptor alpha expression was significantly decreased, and exogenous
IL-2 only partially rescued the CD28 defect. Basal immunoglobulin (Ig) concentrations in CD28-deficient mice were about one-fifth
of those found in wild-type controls, with low titers of IgG1 and IgG2b but an increase in IgG2a. In addition, activity of
T helper cells in CD28-/- mice was reduced and immunoglobulin class switching was diminished after infection with vesicular
stomatitis virus. However, cytotoxic T cells could still be induced and the mice showed delayed-type hypersensitivity after
infection with lymphocytic choriomeningitis virus. Thus, CD28 is not required for all T cell responses in vivo, suggesting
that alternative costimulatory pathways may exist.
Progress toward understanding the biology of prostate cancer has been slow due to the few animal research models available to study the spectrum of this uniquely human disease. To develop an animal model for prostate cancer, several lines of transgenic mice were generated by using the prostate-specific rat probasin promoter to derive expression of the simian virus 40 large tumor antigen-coding region. Mice expressing high levels of the transgene display progressive forms of prostatic disease that histologically resemble human prostate cancer, ranging from mild intraepithelial hyperplasia to large multinodular malignant neoplasia. Prostate tumors have been detected specifically in the prostate as early as 10 weeks of age. Immunohistochemical analysis of tumor tissue has demonstrated that dorsolateral prostate-specific secretory proteins were confined to well-differentiated ductal epithelial cells adjacent to, or within, the poorly differentiated tumor mass. Prostate tumors in the mice also display elevated levels of nuclear p53 and a decreased heterogeneous pattern of androgen-receptor expression, as observed in advanced human prostate cancer. The establishment of breeding lines of transgenic mice that reproducibly develop prostate cancer provides an animal model system to study the molecular basis of transformation of normal prostatic cells and the factors influencing the progression to metastatic prostate cancer.
This study investigated the generation of primary tumor-specific CTL activity in vitro to several mouse tumors. We report that the development of optimal primary tumor-specific CTL to the P815 mastocytoma, the EL4 thymoma, and the Lewis lung carcinoma is dependent on tumor Ags, on enhancement of T cell costimulation by B7.1, and on exogenous T helper activity in the form of IL-2 and IL-4. A relatively low concentration of IL-2 and IL-4 was required to limit the induction of lymphokine-activated killer cells. In the case of P815, the CTL were directed toward molecularly defined tumor rejection Ags. These primary cultures yielded long term T cell lines that were heterogeneous in fine tumor Ag specificity and in cytokine production.
One reason for the poor immunogenicity of many tumors may be that they cannot provide signals for CD28-mediated costimulation necessary to fully activate T cells. It has recently become apparent that CTLA-4, a second counterreceptor for the B7 family of costimulatory molecules, is a negative regulator of T cell activation. Here, in vivo administration of antibodies to CTLA-4 resulted in the rejection of tumors, including preestablished tumors. Furthermore, this rejection resulted in immunity to a secondary exposure to tumor cells. These results suggest that blockade of the inhibitory effects of CTLA-4 can allow for, and potentiate, effective immune responses against tumor cells.
Co-stimulation via the CD28/CTLA-4 system appears critical for T cell proliferation to peptide antigens presented in association
with MHC. In this study, we examine the roles of CD28 and CTLA-4 in the response of murine T cells to the superantigen staphylococcal
enterotoxin B (SEB). In vitro, antibodies against B7-1/B7-2 or Fab fragments of anti-CD28 antibodies significantly inhibit the response of splenocytes
to SEB. Conversely, Fab fragments of anti-CTLA-4 antibodies augment the proliferative response. Further, addition of blocking
antibodies directed against B7-1/B7-2 augment proliferation co-stimulated by intact anti-CD28 antibodies. These data support
the hypothesis that CD28 and CTLA-4 exert opposing effects upon early T cell activation. In vivo, Intact anti-CD28 antibodies and non-stimulatory Fab fragments of anti-CD28 appear to have similar inhibitory effects upon
the expansion of Vβ8+ T cells. In contrast, both intact and Fab fragments of anti-CTLA-4 appear to amplify this expansion. We conclude that the
SEB response is significantly augmented by CD28-derived signaling and this in turn may be attenuated by signals through CTLA-4.
The B7 family of cell surface molecules expressed on APC provides accessory signals to T cells via either CD28 or CTLA-4. However, while CD28 transduces a costimulatory signal that is required for an optimal immune response, CTLA-4 transmits a negative signal. These studies use an anti-CTLA-4 mAb to directly address the role of this T cell surface molecule in experimental allergic encephalomyelitis (EAE). CTLA-4 regulation of disease was assessed during initial immune cell interactions and during the effector stage of the encephalitogenic immune response. The effects of anti-CTLA-4 treatment were schedule dependent. CTLA-4 blockade during the onset of clinical symptoms markedly exacerbated disease, enhancing mortality. Disease exacerbation was associated with enhanced production of the encephalitogenic cytokines TNF-alpha, IFN-gamma and IL-2. Hence, CTLA-4 regulates the intensity of the autoimmune response in EAE, attenuating inflammatory cytokine production and clinical disease manifestations.
Humoral immune responses were characterized in mouse strains lacking either or both B7 molecules. Mice deficient in both B7-1 and B7-2 failed to generate antigen-specific IgG1 and IgG2a responses and lacked germinal centers when immunized by a number of routes and even in the presence of complete Freund's adjuvant. These results demonstrate that B7-mediated signaling plays a critical role in germinal center formation and immunoglobulin class switching in vivo. Mice lacking only B7-1 or B7-2 mounted high-titer antigen-specific IgG responses when immunized in complete Freund's adjuvant, indicating that B7-1 and B7-2 can have overlapping, compensatory functions for IgG responses. When immunized intravenously without adjuvant, B7-2-deficient mice failed to switch antibody isotypes or form germinal centers, whereas B7-1-deficient mice gave antibody responses comparable with wild-type mice. Thus, B7-2 has an important role in initiating antibody responses in the absence of adjuvant, but the induction of B7-1 by adjuvant in B7-2-deficient mice can compensate for the absence of B7-2.
Recent studies indicate that CTLA-4 interaction with B7 ligands transduces an inhibitory signal to T lymphocytes. Mice homozygous for a null mutation in CTLA-4 have provided the most dramatic example of the functional importance of CTLA-4 in vivo. These animals develop a fatal lymphoproliferative disorder and were reported to have an increase in CD4(+) and CD8(+) thymocytes and CD4(-)CD8(-) thymocytes, and a decrease in CD4(+)CD8(+) thymocytes. Based on these observations, it was proposed that CTLA-4 is necessary for normal thymocyte development. In this study, CTLA-4-deficient mice carrying an insertional mutation into exon 3 of the ctla-4 gene were generated. Although these mice display a lymphoproliferative disorder similar to previous reports, there was no alteration in the thymocyte profiles when the parathymic lymph nodes were excluded from the thymi. Further, thymocyte development was normal throughout ontogeny and in neonates, and there was no increase in thymocyte production. Finally, T cell antigen receptor signaling, as assessed by proximal and distal events, was not altered in thymocytes from CTLA-4(-/-) animals. Collectively, these results clearly demonstrate that the abnormal T cell expansion in the CTLA-4-deficient mice is not due to altered thymocyte development and suggest that the apparent altered thymic phenotype previously described was due to the inclusion of parathymic lymph nodes and, in visibly ill animals, to the infiltration of the thymus by activated peripheral T cells. Thus it appears that CTLA-4 is primarily involved in the regulation of peripheral T cell activation.
Generation of a T cell-mediated antitumor response depends on T cell receptor engagement by major histocompatibility complex/antigen as well as CD28 ligation by B7. CTLA-4 is a second B7 receptor expressed by T cells upon activation that, unlike CD28, appears to deliver an inhibitory signal to T cells. Recently, we and others demonstrated that administration of an anti-CTLA-4 antibody was sufficient to promote regression of several murine tumors. However, certain tumors, such as the SM1 mammary carcinoma, remain refractory to this type of immunotherapy. In the present study, we report that the combination of both CTLA-4 blockade and a vaccine consisting of granulocyte-macrophage colony-stimulating factor-expressing SM1 cells resulted in regression of parental SM1 tumors, despite the ineffectiveness of either treatment alone. This synergistic therapy resulted in long-lasting immunity to SM1 and depended on both CD4(+) and CD8(+) T cells. Interestingly, synergy was not observed between CTLA-4 and a B7-expressing SM1 vaccine. Given that granulocyte-macrophage colony-stimulating factor promotes differentiation and activation of dendritic cells as well as enhances cross-priming of T cells to tumor-derived antigens and that SM1 is major histocompatibility complex class II-negative, our findings suggest that CTLA-4 blockade acts at the level of a host-derived antigen-presenting cell. In addition, these results also support the idea that the most effective and synergistic vaccine strategy targets treatments that enhance T cell priming at the level of host-derived antigen-presenting cells.
Ox-40 and Ox-40 ligand (Ox-40L) are thought to be involved in T cell-APC interactions. However, their exact role in T cell responses is undefined. Using fibroblast transfectants expressing Ox-40L and/or B7-1, and CD4 cells from TCR transgenic mice, we investigated the effect of Ox-40 signaling on primary responses to the Ag pigeon cytochrome c. Ox-40 expression on naive CD4 cells peaked 2 to 3 days after activation, and was lost by 4 to 5 days. APCs with Ox-40L promoted partial activation of naive T cells with some IL-2 secretion, but were unable to enhance proliferation, unlike those with B7-1. APCs coexpressing Ox-40L with B7-1 induced large quantities of IL-2 and promoted proliferative responses that persisted for several days. Effector cells taken 5 days after naive T cell activation reexpressed Ox-40 within 4 h and responded strongly to APCs expressing Ox-40L, whereas B7-1 had little effect. Synergy was also seen between Ox-40L and B7-1, with primarily IL-2 being elevated, although IL-4 and IL-5 were also up-regulated. The most striking action was on effector T cell proliferation, which continued at high levels for up to 4 days, with little proliferation evident at this time in the absence of Ox-40 signals. These data suggest that Ox-40/Ox-40L interactions act after initial activation events to prolong clonal expansion and enhance effector cytokine secretion, and may be involved in promoting long-lived primary CD4 responses.
We have previously shown that antibodies to CTLA-4, an inhibitory receptor on T cells, can be effective at inducing regression of transplantable murine tumors. In this study, we demonstrate that an effective immune response against primary prostate tumors in transgenic (TRAMP) mice can be elicited using a strategy that combines CTLA-4 blockade and an irradiated tumor cell vaccine. Treatment of TRAMP mice at 14 weeks of age resulted in a significant reduction in tumor incidence (15% versus control, 75%), as assessed 2 months after treatment. Histopathological analysis revealed that treated mice had a lower tumor grade with significant accumulation of inflammatory cells in interductal spaces when treated with anti-CTLA-4 and a granulocyte-macrophage colony-stimulating factor-expressing vaccine. Vaccination of nontransgenic mice with this regimen resulted in marked prostatitis accompanied by destruction of epithelium, indicating that the immune response was, at least in part, directed against normal prostate antigens. These findings demonstrate that this combinatorial treatment can elicit a potent antiprostate response and suggest potential of this approach for treatment of prostate cancer.
The T cell compartment of adaptive immunity provides vertebrates with the potential to survey for and respond specifically to an incredible diversity of antigens. The T cell repertoire must be carefully regulated to prevent unwanted responses to self. In the periphery, one important level of regulation is the action of costimulatory signals in concert with T cell antigen-receptor (TCR) signals to promote full T cell activation. The past few years have revealed that costimulation is quite complex, involving an integration of activating signals and inhibitory signals from CD28 and CTLA-4 molecules, respectively, with TCR signals to determine the outcome of a T cell's encounter with antigen. Newly emerging data suggest that inhibitory signals mediated by CTLA-4 not only can determine whether T cells become activated, but also can play a role in regulating the clonal representation in a polyclonal response. This review primarily focuses on the cellular and molecular mechanisms of regulation by CTLA-4 and its manipulation as a strategy for tumor immunotherapy.
T cell anergy is a tolerance mechanism in which the lymphocyte is intrinsically functionally inactivated following an antigen encounter, but remains alive for an extended period of time in a hyporesponsive state. Models of T cell anergy affecting both CD4(+) and CD8(+) cells fall into two broad categories. One, clonal anergy, is principally a growth arrest state, whereas the other, adaptive tolerance or in vivo anergy, represents a more generalized inhibition of proliferation and effector functions. The former arises from incomplete T cell activation, is mostly observed in previously activated T cells, is maintained by a block in the Ras/MAP kinase pathway, can be reversed by IL-2 or anti-OX40 signaling, and usually does not result in the inhibition of effector functions. The latter is most often initiated in naïve T cells in vivo by stimulation in an environment deficient in costimulation or high in coinhibition. Adaptive tolerance can be induced in the thymus or in the periphery. The cells proliferate and differentiate to varying degrees and then downregulate both functions in the face of persistent antigen. The state involves an early block in tyrosine kinase activation, which predominantly inhibits calcium mobilization, and an independent mechanism that blocks signaling through the IL-2 receptor. Adaptive tolerance reverses in the absence of antigen. Aspects of both of the anergic states are found in regulatory T cells, possibly preventing them from dominating initial immune responses to foreign antigens and shutting down such responses prematurely.
For decades urologists have successfully used immunotherapy in the battle against cancer. Interleukin-2 in renal cell carcinoma and bacillus Calmette-Guerin in bladder cancer are standard primary and/or adjunctive therapies for these diseases. Recent advances in our understanding of mechanisms governing immune system activation have fostered a myriad of novel immunotherapeutic approaches that show great promise in vivo but have had limited success in human trials to date. This review highlights current immunotherapy strategies that may prove to be successful treatments for urological cancers.
We performed a MEDLINE literature search for articles relating to immunotherapy in bladder, prostate and renal cell carcinoma in animals and humans. We included the most promising developments in this review.
In addition to combining existing therapies to improve their efficacy, novel approaches that attempt to exploit the immune system ability to identify, target and eradicate malignancies are now being developed. These therapies include the use of antitumoral monoclonal and bi-specific antibodies, manipulation of T-lymphocyte costimulatory molecules and the administration of newly discovered cytokines as well as the development of antitumor vaccines.
To date the full potential of immunotherapy for the treatment of urological malignancies has not been recognized. As our knowledge of the immune system expands, so too may our ability to manipulate it to affect tumor regression. This review describes the most recent and most promising developments in immunotherapy for urological malignancies.
Co-signalling molecules are cell-surface glycoproteins that can direct, modulate and fine-tune T-cell receptor (TCR) signals. On the basis of their functional outcome, co-signalling molecules can be divided into co-stimulators and co-inhibitors, which promote or suppress T-cell activation, respectively. By expression at the appropriate time and location, co-signalling molecules positively and negatively control the priming, growth, differentiation and functional maturation of a T-cell response. We are now beginning to understand the power of co-inhibitors in the context of lymphocyte homeostasis and the pathogenesis of human diseases. In this article, I focus on several newly described co-inhibitory pathways in the B7–CD28 family.
Nineteen patients with high-risk resected stage III and IV melanoma were immunized with three tumor antigen epitope peptides from gp100, MART-1, and tyrosinase emulsified with adjuvant Montanide ISA 51 and received a fully human anti-cytotoxic T-lymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody MDX-010. Each of three cohorts received escalating doses of antibody with vaccine primarily to evaluate the toxicities and maximum-tolerated dose (MTD) of MDX-010 with vaccine. MDX-010 pharmacokinetics and immune responses were secondary end points.
Peptide immunizations with MDX-010 were administered every 4 weeks for 6 months and then every 12 weeks for 6 months. A leukapheresis to obtain peripheral-blood mononuclear cells for immune analyses was performed before treatment and after the sixth vaccination. Patients were observed until relapse.
Grade 3 gastrointestinal (GI) toxicity (diarrhea or abdominal pain) was observed in three patients in the highest dose cohort and one in the middle dose cohort who seemed to be autoimmune. That defined the MTD with vaccine on this schedule at 1 mg/kg. Of eight patients with evidence of autoimmunity, three have experienced disease relapse. Of 11 patients without autoimmune symptoms, nine have experienced disease relapse. Significant immune responses were measured by tetramer and enzyme-linked immunospot assays against gp100 and MART-1.
Dose-related autoimmune adverse events, predominantly skin and GI toxicities, were reversible. Patients mounted an antigen-specific immune response to a peptide vaccine when combined with a human anti-CTLA-4 antibody.
The main focus of the Symposium was the fact that cell types of the innate and adaptive immune systems can have tumor-favoring as well as tumor antagonistic effects, both in a preventive and therapeutic mode. It was shown that macrophages (Mphi) and dendritic cells within a tumor exert tumor-favoring effects through the action of certain cytokines. Inflammatory reactions could favor the onset and growth of tumors. Dual immune functions were shown with CD4+ T cells and certain matrix metalloproteinase (MMP) activities favoring tumor progression and CD8+ T cells and certain heat shock proteins having antitumor action. Lack of antitumor action despite positive immune stimulation was also shown to depend on the existence of barriers to tumor infiltration by lymphocytes; remodeling of vasculature, e.g., by IFNgamma-induced cytokines like MIG and IPIO, reversed this type of impediment. Certain CXC cytokines increased tumor progression, whereas others, particularly those induced by IFNgamma, had the opposite effect; stromal-derived factor-1 and its receptor CXCR4 affected tumor propensity to metastasize in certain organs. Stromal-derived factor-1 induced MMP9, which in turn regulated the bioavailability of vascular endothelial growth factor and the cascade of its tumor-favoring effects, whereas granulocyte colony-stimulating factor decreased MMP9 and the consequences of its action. The effects of certain proinflammatory cytokines and vascular endothelial growth factor functions in angiogenesis and lymphoangiogenesis were also discussed. The favoring effects of fever-like thermal stress on the function of molecules instrumental in lymphoid cell adhesion to vessels and infiltration into sites of immune actions were described. The mechanisms involved in the development of immune memory and those conditioning Type I and CTL responses were also discussed. A number of presentations were concerned with laboratory studies aimed at developing clinical regimens with potential activity in the prevention or treatment of cancer. Prevention of Her2/neu breast cancer in transgenic mice was achieved by suitable regimens with IL12 combined with vaccines, including DNA-based vaccines administered in conjunction with electroporation. Vaccination with shared tumor antigen MUCI or cyclin B was discussed, and its clinical translation was described. The prevention of TRAMP prostate tumor in transgenic mice by anti-CTLA4 antibody plus vaccine was described, as was the translation of these regimens to the clinics. Clinical successes in melanoma patients using antimelanoma antigen antibodies in a therapeutic mode and precautions to be exerted in evaluating in vivo immune responses based on in vitro assays were emphasized. The symposium was concluded with an overall discussion focused on basic questions related to the capability of immunity to exert tumor-favoring or antitumor effects depending on conditions determined by both tumor and host functions.
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