Publications (61)243.29 Total impact
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Article: Mucosal Imprinting of Vaccine-Induced CD8+ T Cells Is Crucial to Inhibit the Growth of Mucosal Tumors.
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ABSTRACT: Although many human cancers are located in mucosal sites, most cancer vaccines are tested against subcutaneous tumors in preclinical models. We therefore wondered whether mucosa-specific homing instructions to the immune system might influence mucosal tumor outgrowth. We showed that the growth of orthotopic head and neck or lung cancers was inhibited when a cancer vaccine was delivered by the intranasal mucosal route but not the intramuscular route. This antitumor effect was dependent on CD8(+) T cells. Indeed, only intranasal vaccination elicited mucosal-specific CD8(+) T cells expressing the mucosal integrin CD49a. Blockade of CD49a decreased intratumoral CD8(+) T cell infiltration and the efficacy of cancer vaccine on mucosal tumor. We then showed that after intranasal vaccination, dendritic cells from lung parenchyma, but not those from spleen, induced the expression of CD49a on cocultured specific CD8(+) T cells. Tumor-infiltrating lymphocytes from human mucosal lung cancer also expressed CD49a, which supports the relevance and possible extrapolation of these results in humans. We thus identified a link between the route of vaccination and the induction of a mucosal homing program on induced CD8(+) T cells that controlled their trafficking. Immunization route directly affected the efficacy of the cancer vaccine to control mucosal tumors.Science translational medicine 02/2013; 5(172):172ra20. · 7.80 Impact Factor -
Article: Trial watch: Cardiac glycosides and cancer therapy.
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ABSTRACT: Cardiac glycosides (CGs) are natural compounds sharing the ability to operate as potent inhibitors of the plasma membrane Na(+)/K(+)-ATPase, hence promoting-via an indirect mechanism-the intracellular accumulation of Ca(2+) ions. In cardiomyocytes, increased intracellular Ca(2+) concentrations exert prominent positive inotropic effects, that is, they increase myocardial contractility. Owing to this feature, two CGs, namely digoxin and digitoxin, have extensively been used in the past for the treatment of several cardiac conditions, including distinct types of arrhythmia as well as contractility disorders. Nowadays, digoxin is approved by the FDA and indicated for the treatment of congestive heart failure, atrial fibrillation and atrial flutter with rapid ventricular response, whereas the use of digitoxin has been discontinued in several Western countries. Recently, CGs have been suggested to exert potent antineoplastic effects, notably as they appear to increase the immunogenicity of dying cancer cells. In this Trial Watch, we summarize the mechanisms that underpin the unsuspected anticancer potential of CGs and discuss the progress of clinical studies that have evaluated/are evaluating the safety and efficacy of CGs for oncological indications.Oncoimmunology. 02/2013; 2(2):e23082. -
Article: NK cells from pleural effusions are potent antitumor effector cells.
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ABSTRACT: Natural killer (NK) cells express a set of activating and inhibitory receptors which, after interaction with their ligands, determine whether or not the target cell will be lysed. Many studies have clearly demonstrated that NK cells have the capacity to lyse stressed cells (such as tumor or virally-infected cells). However, NK cells that infiltrate tumors usually exhibit phenotypic and functional defects. In this issue of the European Journal of Immunology, Vacca et al. [Eur. J. Immunol. 2013. 43: XXXX-XXXX] show that NK cells in pleural effusions of primary and metastatic tumors of various origins are not anergic, possibly because the downregulation of activating receptors and the upregulation of inhibitory receptors does not occur, as previously reported for tumor NK cells. Another major finding of this study is the capacity of these pleural NK cells to respond to IL-2 stimulation, as the authors demonstrate that pleural NK cells stimulated by IL-2 in long-term culture acquire the capacity to lyse autologous tumor cells isolated from pleural effusions. These results support the treatment of primary or metastatic pleural tumors with IL-2 or other innovative strategies currently being developed to stimulate NK cells in cancer patients as discussed in this Commentary.European Journal of Immunology 01/2013; · 5.10 Impact Factor -
Article: [Cancers of the upper aerodigestive tract associated with human papillomavirus].
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ABSTRACT: Carcinomas of the aerodigestive tract are most often secondary to alcohol and tobacco intoxication. However, it is shown that the oncogenic human papillomavirus (HPV) have an increasing role in the carcinogenesis of these cancers. Patients with HPV+ carcinoma are generally younger and not alcohol and tobacco users. These carcinomas are mainly localized in the oropharynx and in particular at the tonsil. HPV is found in 40 to 90 % of the cancers in the oropharynx, depending on the country. These HPV+ carcinomas have a better prognosis with better radio or chemosensitivity. To date, no change of treatment is recommended, however, several trials are underway. Preventive vaccination of boys is a real public health issue, especially since it is recommended in some countries. Moreover, a better understanding of the tumor microenvironment will ultimately offer therapeutic vaccination.Medecine sciences: M/S 01/2013; 29(1):83-8. · 0.64 Impact Factor -
Article: Trial watch: Peptide vaccines in cancer therapy.
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ABSTRACT: Prophylactic vaccination constitutes one of the most prominent medical achievements of history. This concept was first demonstrated by the pioneer work of Edward Jenner, dating back to the late 1790s, after which an array of preparations that confer life-long protective immunity against several infectious agents has been developed. The ensuing implementation of nation-wide vaccination programs has de facto abated the incidence of dreadful diseases including rabies, typhoid, cholera and many others. Among all, the most impressive result of vaccination campaigns is surely represented by the eradication of natural smallpox infection, which was definitively certified by the WHO in 1980. The idea of employing vaccines as anticancer interventions was first theorized in the 1890s by Paul Ehrlich and William Coley. However, it soon became clear that while vaccination could be efficiently employed as a preventive measure against infectious agents, anticancer vaccines would have to (1) operate as therapeutic, rather than preventive, interventions (at least in the vast majority of settings), and (2) circumvent the fact that tumor cells often fail to elicit immune responses. During the past 30 y, along with the recognition that the immune system is not irresponsive to tumors (as it was initially thought) and that malignant cells express tumor-associated antigens whereby they can be discriminated from normal cells, considerable efforts have been dedicated to the development of anticancer vaccines. Some of these approaches, encompassing cell-based, DNA-based and purified component-based preparations, have already been shown to exert conspicuous anticancer effects in cohorts of patients affected by both hematological and solid malignancies. In this Trial Watch, we will summarize the results of recent clinical trials that have evaluated/are evaluating purified peptides or full-length proteins as therapeutic interventions against cancer.Oncoimmunology. 12/2012; 1(9):1557-1576. -
Dataset: dendritic cell based cancer therapy
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Dataset: onci-1-1111
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Article: PD-1-expressing tumor-infiltrating T cells are a favorable prognostic biomarker in HPV associated head and neck cancer.
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ABSTRACT: Head and neck cancers positive for human papilloma virus (HPV) have a more favorable clinical outcome than HPV-negative cancers, but it is unknown why this is the case. We hypothesized that prognosis was affected by intrinsic features of HPV-infected tumor cells or differences in host immune response. In this study, we focused on a comparison of regulatory Foxp3+T cells and PD-1+T cells in the microenvironment of tumors that were positive or negative for HPV, in two groups that were matched for various clinical and biological parameters. HPV-positive head and neck cancers were more heavily infiltrated by regulatory T cells and PD-1+ T cells in this group were positively correlated with a favorable clinical outcome. In explaining this paradoxical result, we showed that these PD-1+T cells expressed activation markers and were functional after blockade of the PD-1-PDL-1 axis in vitro. Approximately 50% of PD-1+ tumor-infiltrating T cells lacked Tim-3 expression and may indeed represent activated T cells. In mice, administration of a cancer vaccine increased PD-1 on T cells with concomitant tumor regression. In this setting, PD-1 blockade synergized with vaccine in eliciting antitumor efficacy. Our findings prompt a need to revisit the significance of PD-1-infiltrating T cells in cancer, where we suggest that PD-1 detection may reflect a previous immune responses against tumors that might be reactivated by PD-1/PD-L1 blockade.Cancer Research 11/2012; · 7.86 Impact Factor -
Article: Trial watch: Prognostic and predictive value of the immune infiltrate in cancer.
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ABSTRACT: Solid tumors are constituted of a variety of cellular components, including bona fide malignant cells as well as endothelial, structural and immune cells. On one hand, the tumor stroma exerts major pro-tumorigenic and immunosuppressive functions, reflecting the capacity of cancer cells to shape the microenvironment to satisfy their own metabolic and immunological needs. On the other hand, there is a component of tumor-infiltrating leucocytes (TILs) that has been specifically recruited in the attempt to control tumor growth. Along with the recognition of the critical role played by the immune system in oncogenesis, tumor progression and response to therapy, increasing attention has been attracted by the potential prognostic and/or predictive role of the immune infiltrate in this setting. Data from large clinical studies demonstrate indeed that a robust infiltration of neoplastic lesions by specific immune cell populations, including (but not limited to) CD8(+) cytotoxic T lymphocytes, Th1 and Th17 CD4(+) T cells, natural killer cells, dendritic cells, and M1 macrophages constitutes an independent prognostic indicator in several types of cancer. Conversely, high levels of intratumoral CD4(+)CD25(+)FOXP3(+) regulatory T cells, Th2 CD4(+) T cells, myeloid-derived suppressor cells, M2 macrophages and neutrophils have frequently been associated with dismal prognosis. So far, only a few studies have addressed the true predictive potential of TILs in cancer patients, generally comforting the notion that-at least in some clinical settings-the immune infiltrate can reliably predict if a specific patient will respond to therapy or not. In this Trial Watch, we will summarize the results of clinical trials that have evaluated/are evaluating the prognostic and predictive value of the immune infiltrate in the context of solid malignancies.Oncoimmunology. 11/2012; 1(8):1323-1343. -
Article: VEGFA-VEGF Receptor pathway blockade inhibits tumor-induced regulatory T cell proliferation in colorectal cancer.
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ABSTRACT: Multi-target anti-angiogenic tyrosine kinase inhibitors (TKI) have been shown to reduce regulatory T cells (Treg) in tumor-bearing animals and metastatic renal carcinoma patients. However, a direct role of the VEGF-A/VEGFR pathway inhibition in this phenomenon is a matter of debate and molecular mechanisms leading to Treg modulation in this setting have not been explored to date. Treg proportion, number and proliferation were analyzed by flow cytometry in peripheral blood of metastatic colorectal cancer (mCRC) patients treated with bevacizumab, a monoclonal antibody (mab) targeting specifically VEGF-A, and in colon cancer-bearing mice (CT26) treated with drugs targeting the VEGF/VEGFR axis. The direct impact of VEGF-A on Treg induction was assessed together with specific blockade of different isoforms of VEGFRs that may be involved. In CT26-bearing mice, anti-VEGF antibody and sunitinib treatments reduced Treg but masitinib, a TKI not targeting VEGFR, did not. Targeting VEGF-A/VEGFR axis seems sufficient to affect Treg percentages, without any changes in their function. Similarly, bevacizumab inhibited Treg accumulation in peripheral blood of mCRC patients. In vitro, Treg expressing VEGFR from tumor-bearing mice directly proliferated in response to VEGF-A. Anti-VEGF-A treatment decreased Treg proliferation in mice as well as in mCRC patients. VEGFR2 but not VEGFR1 specific blockade led to the same results. We identified a novel mechanism of tumor escape by which VEGF-A directly triggers Treg proliferation. This proliferation is inhibited by VEGF-A/VEGFR2 blockade. Anti-VEGF-A therapies also have immunological effects that may be used with a therapeutic goal in the future.Cancer Research 10/2012; · 7.86 Impact Factor -
Article: Universal cancer peptide-based therapeutic vaccine breaks tolerance against telomerase and eradicates established tumor.
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ABSTRACT: PURPOSE: To evaluate CD4+ helper functions and antitumor effect of promiscuous universal cancer peptides (UCP) derived from telomerase reverse transcriptase (TERT). EXPERIMENTAL DESIGN: To evaluate the widespread immunogenicity of UCPs in human, spontaneous T cell responses against UCPs were measured in various types of cancer using T cell proliferation and ELISPOT assays. The humanized HLA-DRB1*0101/HLA-A*0201 transgenic mice was used to study CD4+ helper effects of UCPs on antitumor CTL responses. UCP-based antitumor therapeutic vaccine was evaluated using an HLA-A*0201positive B16 melanoma that express TERT. RESULTS: Presence of high number of UCP-specific CD4+ T cells was found in the blood of patients with various types of cancer. These UCP-specific T cells mainly produce IFN-γ and TNF- . In HLA transgenic mice, UCPs vaccinations induce high avidity CD4+ Th1 cells and activated dendritic cells that produced interleukin 12. UCP-based vaccination breaks self tolerance against TERT and enhances primary and memory CTL responses. Furthermore, the use of UCP strongly improves the efficacy of therapeutic vaccination against established B16-HLA-A*0201 melanoma and promotes tumor infiltration by TERT-specific CD8+ TILs. CONCLUSIONS: Ours results showed that UCP-based vaccinations strongly stimulate antitumor immune responses and could be used to design efficient immunotherapies in multiple types of cancers.Clinical Cancer Research 10/2012; · 7.74 Impact Factor -
Article: Trial watch: Dendritic cell-based interventions for cancer therapy.
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ABSTRACT: Dendritic cells (DCs) occupy a central position in the immune system, orchestrating a wide repertoire of responses that span from the development of self-tolerance to the elicitation of potent cellular and humoral immunity. Accordingly, DCs are involved in the etiology of conditions as diverse as infectious diseases, allergic and autoimmune disorders, graft rejection and cancer. During the last decade, several methods have been developed to load DCs with tumor-associated antigens, ex vivo or in vivo, in the attempt to use them as therapeutic anticancer vaccines that would elicit clinically relevant immune responses. While this has not always been the case, several clinical studies have demonstrated that DC-based anticancer vaccines are capable of activating tumor-specific immune responses that increase overall survival, at least in a subset of patients. In 2010, this branch of clinical research has culminated with the approval by FDA of a DC-based therapeutic vaccine (sipuleucel-T, Provenge(®)) for use in patients with asymptomatic or minimally symptomatic metastatic hormone-refractory prostate cancer. Intense research efforts are currently dedicated to the identification of the immunological features of patients that best respond to DC-based anticancer vaccines. This knowledge may indeed lead to personalized combination strategies that would extend the benefit of DC-based immunotherapy to a larger patient population. In addition, widespread enthusiasm has been generated by the results of the first clinical trials based on in vivo DC targeting, an approach that holds great promises for the future of DC-based immunotherapy. In this Trial Watch, we will summarize the results of recently completed clinical trials and discuss the progress of ongoing studies that have evaluated/are evaluating DC-based interventions for cancer therapy.Oncoimmunology. 10/2012; 1(7):1111-1134. -
Article: Trial watch: FDA-approved Toll-like receptor agonists for cancer therapy.
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ABSTRACT: Toll-like receptors (TLRs) have first been characterized for their capacity to detect conserved microbial components like lipopolysaccharide (LPS) and double-stranded RNA, resulting in the elicitation of potent (innate) immune responses against invading pathogens. More recently, TLRs have also been shown to promote the activation of the cognate immune system against cancer cells. Today, only three TLR agonists are approved by FDA for use in humans: the bacillus Calmette-Guérin (BCG), monophosphoryl lipid A (MPL) and imiquimod. BCG (an attenuated strain of Mycobacterium bovis) is mainly used as a vaccine against tuberculosis, but also for the immunotherapy of in situ bladder carcinoma. MPL (derived from the LPS of Salmonella minnesota) is included in the formulation of Cervarix®, a vaccine against human papillomavirus-16 and -18. Imiquimod (a synthetic imidazoquinoline) is routinely employed for actinic keratosis, superficial basal cell carcinoma, and external genital warts (condylomata acuminata). In this Trial Watch, we will summarize the results of recently completed clinical trials and discuss the progress of ongoing studies that have evaluated/are evaluating FDA-approved TLR agonists as off-label medications for cancer therapy.Oncoimmunology. 09/2012; 1(6):894-907. -
Article: Trial Watch: Experimental Toll-like receptor agonists for cancer therapy.
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ABSTRACT: Toll-like receptors (TLRs) are prototypic pattern recognition receptors (PRRs) best known for their ability to activate the innate immune system in response to conserved microbial components such as lipopolysaccharide and double-stranded RNA. Accumulating evidence indicates that the function of TLRs is not restricted to the elicitation of innate immune responses against invading pathogens. TLRs have indeed been shown to participate in tissue repair and injury-induced regeneration as well as in adaptive immune responses against cancer. In particular, TLR4 signaling appears to be required for the efficient processing and cross-presentation of cell-associated tumor antigens by dendritic cells, which de facto underlie optimal therapeutic responses to some anticancer drugs. Thus, TLRs constitute prominent therapeutic targets for the activation/intensification of anticancer immune responses. In line with this notion, long-used preparations such as the Coley toxin (a mixture of killed Streptococcus pyogenes and Serratia marcescens bacteria) and the bacillus Calmette-Guérin (BCG, an attenuated strain of Mycobacterium bovis originally developed as a vaccine against tuberculosis), both of which have been associated with consistent anticancer responses, potently activate TLR2 and TLR4 signaling. Today, besides BCG, only one TLR agonist is FDA-approved for therapeutic use in cancer patients: imiquimod. In this Trial Watch, we will briefly present the role of TLRs in innate and cognate immunity and discuss the progress of clinical studies evaluating the safety and efficacy of experimental TLR agonists as immunostimulatory agents for oncological indications.Oncoimmunology. 08/2012; 1(5):699-716. -
Article: Trial Watch: Immunostimulatory cytokines.
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ABSTRACT: During the last two decades, a number of approaches for the activation of the immune system against cancer has been developed. These include highly specific interventions, such as monoclonal antibodies, vaccines and cell-based therapies, as well as relatively unselective strategies, such as the systemic administration of adjuvants and immunomodulatory cytokines. Cytokines constitute a huge group of proteins that, taken together, regulate not only virtually all the aspects of innate and cognate immunity, but also several other cellular and organismal functions. Cytokines operate via specific transmembrane receptors that are expressed on the plasma membrane of target cells and, depending on multiple variables, can engage autocrine, paracrine or endocrine signaling pathways. The most appropriate term for defining the cytokine network is "pleiotropic": cytokines are produced by - and operate on - multiple, often overlapping, cell types, triggering context-depend biological outcomes as diverse as cell proliferation, chemotaxis, differentiation, inflammation, elimination of pathogens and cell death. Moreover, cytokines often induce the release of additional cytokines, thereby engaging self-amplificatory or self-inhibitory signaling cascades. In this Trial Watch, we will summarize the biological properties of cytokines and discuss the progress of ongoing clinical studies evaluating their safety and efficacy as immunomodulatory agents against cancer.Oncoimmunology. 07/2012; 1(4):493-506. -
Article: Comprehensive analysis of current approaches to inhibit regulatory T cells in cancer.
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ABSTRACT: CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) have emerged as a dominant T cell population inhibiting anti-tumor effector T cells. Initial strategies used for Treg-depletion (cyclophosphamide, anti-CD25 mAb…) also targeted activated T cells, as they share many phenotypic markers. Current, ameliorated approaches to inhibit Treg aim to either block their function or their migration to lymph nodes and the tumor microenvironment. Various drugs originally developed for other therapeutic indications (anti-angiogenic molecules, tyrosine kinase inhibitors,etc) have recently been discovered to inhibit Treg. These approaches are expected to be rapidly translated to clinical applications for therapeutic use in combination with immunomodulators.Oncoimmunology. 05/2012; 1(3):326-333. -
Article: Trial Watch: Adoptive cell transfer immunotherapy.
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ABSTRACT: During the last two decades, several approaches for the activation of the immune system against cancer have been developed. These include rather unselective maneuvers such as the systemic administration of immunostimulatory agents (e.g., interleukin-2) as well as targeted interventions, encompassing highly specific monoclonal antibodies, vaccines and cell-based therapies. Among the latter, adoptive cell transfer (ACT) involves the selection of autologous lymphocytes with antitumor activity, their expansion/activation ex vivo, and their reinfusion into the patient, often in the context of lymphodepleting regimens (to minimize endogenous immunosuppression). Such autologous cells can be isolated from tumor-infiltrating lymphocytes or generated by manipulating circulating lymphocytes for the expression of tumor-specific T-cell receptors. In addition, autologous lymphocytes can be genetically engineered to prolong their in vivo persistence, to boost antitumor responses and/or to minimize side effects. ACT has recently been shown to be associated with a consistent rate of durable regressions in melanoma and renal cell carcinoma patients and holds great promises in several other oncological settings. In this Trial Watch, we will briefly review the scientific rationale behind ACT and discuss the progress of recent clinical trials evaluating the safety and effectiveness of adoptive cell transfer as an anticancer therapy.Oncoimmunology. 05/2012; 1(3):306-315. -
Article: An unusual human papillomavirus type 82 detection in laryngeal squamous cell carcinoma: case report and review of literature.
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ABSTRACT: Squamous cell carcinoma (SCC) of the larynx is extremely rare in adolescent or younger adult and typically has an aggressive nature. The mechanism of laryngeal oncogenesis is complex and little is known about the role of human papillomaviruses (HPVs) in SCC in young age. HPV infection may occur during birth or latter by oro-genital contact. Most HPV genotypes detected were HPV 6, 11, 16, 18, 33 and 51. Herein, we report a case of invasive laryngeal SCC expressing an HPV 82 in an 18 year-old man with a history of unexplored severe acute dysphonia that started in early childhood.Journal of clinical virology: the official publication of the Pan American Society for Clinical Virology 04/2012; 54(2):190-3. · 3.12 Impact Factor -
Article: Trial watch: Chemotherapy with immunogenic cell death inducers.
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ABSTRACT: The long-established notion that apoptosis would be immunologically silent, and hence it would go unnoticed by the immune system, if not tolerogenic, and hence it would actively suppress immune responses, has recently been revisited. In some instances, indeed, cancer cells undergo apoptosis while emitting a spatiotemporally-defined combination of signals that renders them capable of eliciting a long-term protective antitumor immune response. Importantly, only a few anticancer agents can stimulate such an immunogenic cell death. These include cyclophosphamide, doxorubicin and oxaliplatin, which are currently approved by FDA for the treatment of multiple hematologic and solid malignancies, as well as mitoxantrone, which is being used in cancer therapy and against multiple sclerosis. In this Trial Watch, we will review and discuss the progress of recent (initiated after January 2008) clinical trials evaluating the off-label use of cyclophosphamide, doxorubicin, oxaliplatin and mitoxantrone.Oncoimmunology. 03/2012; 1(2):179-188. -
Article: Trial Watch: Monoclonal antibodies in cancer therapy.
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ABSTRACT: Since the advent of hybridoma technology, dating back to 1975, monoclonal antibodies have become an irreplaceable diagnostic and therapeutic tool for a wide array of human diseases. During the last 15 years, several monoclonal antibodies (mAbs) have been approved by FDA for cancer therapy. These mAbs are designed to (1) activate the immune system against tumor cells, (2) inhibit cancer cell-intrinsic signaling pathways, (3) bring toxins in the close proximity of cancer cells, or (4) interfere with the tumor-stroma interaction. More recently, major efforts have been made for the development of immunostimulatory mAbs that either enhance cancer-directed immune responses or limit tumor- (or therapy-) driven immunosuppression. Some of these antibodies, which are thought to facilitate tumor eradication by initiating or sustaining a tumor-specific immune response, have already entered clinical trials. In this Trial Watch, we will review and discuss the clinical progress of the most important mAbs that are have entered clinical trials after January 2008.Oncoimmunology. 01/2012; 1(1):28-37.
Top co-authors
Top Journals
Institutions
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2012–2013
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Institut de Cancérologie Gustave Roussy
Villejuif, Ile-de-France, France -
Université Paris-Sud 11
Paris, Ile-de-France, France
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2007–2013
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Université Paris Descartes
Paris, Ile-de-France, France
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2004–2009
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Université René Descartes - Paris 5
- Faculté de Médecine
Paris, Ile-de-France, France -
Institut national de la santé et de la recherche médicale
Paris, Ile-de-France, France
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2004–2008
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Hôpital européen Georges-Pompidou – Hôpitaux universitaires Paris-Ouest
Paris, Ile-de-France, France
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2002–2004
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Université Pierre et Marie Curie Paris 6
Paris, Ile-de-France, France
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