-
[show abstract]
[hide abstract]
ABSTRACT: Recent clinical trials have shown promise in the use of chimeric antigen receptor (CAR)-transduced T cells; however, augmentation of their activity may broaden their clinical utility and improve their efficacy. We hypothesized that, since CAR action requires proteins essential for TCR signal transduction, deletion of negative regulators of these signaling pathways would enhance CAR signaling and effector T cell function. We tested CAR activity and function in T cells that lacked one or both isoforms of diacylglycerol kinase (dgk) expressed highly in T cells, dgkα and dgkζ, enzymes that metabolize the second messenger diacylglycerol (DAG) and limit Ras/ERK activation. We found that primary murine T cells transduced with CARs specific for the human tumor antigen mesothelin demonstrated greatly enhanced cytokine production and cytotoxicity when co-cultured with a murine mesothelioma line that stably expresses mesothelin. Additionally, we found that dgk-deficient CAR-transduced T cells were more effective in limiting the growth of implanted tumors, both concurrent with and after establishment of tumor. Consistent with our studies in mice, pharmacologic inhibition of dgks also augments function of primary human T cells transduced with CARs. These results suggest that deletion of negative regulators of TCR signaling enhances the activity and function of CAR-expressing T cells and identify dgks as potential targets for improving the clinical potential of CARs.
Cancer Research 04/2013; · 7.86 Impact Factor
-
Daniel E Schwed Lustgarten,
Charuhas Deshpande,
Charu Aggarwal,
Liang-Chuan Wang,
Vassiliki Saloura,
Anil Vachani,
Li-Ping Wang,
Leslie Litzky,
Michael Feldman,
Jeanette Creaney,
Anna K Nowak,
Corey Langer,
Simona Inghilleri,
Giulia Stella, Steven M Albelda
[show abstract]
[hide abstract]
ABSTRACT: PURPOSE:: Thymidylate synthase (TS) is a potential predictor of outcome after pemetrexed (Pem) in patients with malignant pleural mesothelioma (MPM), and assays measuring TS levels are commercially marketed. The goal of this study was to further evaluate the value of TS and to study another potential biomarker of response, the enzyme, folyl-polyglutamate synthase (FPGS), which activates Pem intracellularly. METHODS:: Levels of TS and FPGS were semi-quantitatively determined immunohistochemically using H-scores on tissue samples from 85 MPM patients receiving Pem as primary therapy. H-score was correlated with radiographic disease control rate (DCR), time to progression (TTP) and overall survival (OS). In addition, expression levels of TS and FPGS in MPM cell lines were determined using immunoblotting and correlated with their sensitivity to Pem-induced cell death. RESULTS:: H-scores from patients with disease control versus progressive disease showed extensive overlap. There were no significant correlations of DCR, TTP, or OS to either TS levels (p = 0.73, 0.93, and 0.59, respectively), FPGS levels (p = 0.95, 0.77, and 0.43, respectively) or the ratio of FPGS/TS using the median scores of each test as cutoffs. There was no correlation between TS or FPGS expression and chemosensitivity of mesothelioma cells to Pem in vitro. CONCLUSIONS:: Although previous retrospective data suggest that TS and FPGS expression might be potential markers of Pem efficacy in MPM, our data indicate these markers lack sufficient predictive value in individual patients and should not be used to guide therapeutic decisions in the absence of prospective studies.
Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 04/2013; 8(4):469-477. · 4.55 Impact Factor
-
Daniel Schwed,
Charuhas Deshpande,
Charu Aggarwal,
Liang-Chuan Wang,
Vassiliki Saloura,
Anil Vachani,
Leslie Litzky,
Michael Feldman,
Jenette Creaney,
Anna Nowak,
Corey Langer,
Giulia M Stella, Steven M Albelda
Journal of Thoracic Oncology 04/2013; 8(4):469-477. · 3.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Background:Species selectivity of DMXAA (5,6-dimethylxanthenone-4-acetic acid, Vadimezan) for murine cells over human cells could explain in part the recent disappointing phase III trials clinical results when preclinical studies were so promising. To identify analogues with greater human clinical potential, we compared the activity of xanthenone-4-acetic acid (XAA) analogues in murine or human cellular models.Methods:Analogues with a methyl group systematically substituted at different positions of the XAA backbone were evaluated for cytokine induction in cultured murine or human leukocytes; and for anti-vascular effects on endothelial cells on matrigel. In vivo antitumour activity and cytokine production by stromal or cancer cells was measured in human A375 and HCT116 xenografts.Results:Mono-methyl XAA analogues with substitutions at the seventh and eighth positions were the most active in stimulating human leukocytes to produce IL-6 and IL-8; and for inhibition of tube formation by ECV304 human endothelial-like cells, while 5- and 6-substituted analogues were the most active in murine cell systems.Conclusion:Xanthenone-4-acetic acid analogues exhibit extreme species selectivity. Analogues that are the most active in human systems are inactive in murine models, highlighting the need for the use of appropriate in vivo animal models in selecting clinical candidates for this class of compounds.
British Journal of Cancer 02/2013; 108(6):1306-15. · 5.04 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The Receptor for Advanced Glycation End Products (RAGE) is a multi-ligand pattern recognition receptor implicated in multiple disease states. Although RAGE is expressed on systemic vascular endothelium, the expression and function of RAGE on lung endothelium has not been studied. Utilizing in vitro (human) and in vivo (mouse) models we established the presence of RAGE on lung endothelium. Because RAGE ligands can induce the expression of RAGE and stored red blood cells (RBCs) express the RAGE ligand Nε-carboxymethyl lysine (Nε -CML) we investigated whether RBC transfusion would augment RAGE expression on endothelium utilizing a syngeneic model of RBC transfusion. RBC transfusion not only increased lung endothelial RAGE expression but enhanced lung inflammation and endothelial activation as lung High Mobility Group Box 1 (HMGB1) and Vascular Cell Adhesion Molecule (VCAM-1) expression was elevated following transfusion. These effects were mediated by RAGE as endothelial activation was absent in RBC transfused RAGE knockout mice. Thus, RAGE is inducibly expressed on lung endothelium and one functional consequence of RBC transfusion is increased RAGE expression and endothelial activation.
AJP Lung Cellular and Molecular Physiology 02/2013; 304(4):L250-63. · 3.66 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Multiple immunotherapy approaches have improved adaptive anti-tumor immune responses in patients with early stage disease; however, results have been less dramatic when treating patients with late stage disease. These blunted responses are likely due to a host of factors, including changes in the tumor microenvironment and systemic immunosuppressive features, which accompany advanced tumor states. We hypothesized that cytoreductive surgery could control these immunosuppressive networks and restore the potency of immunotherapy in advanced disease scenarios.
To test these hypotheses, two representative intratumoral immunotherapies (an adenoviral vector encoding a suicide gene, AdV-tk, or a type-I interferon, Ad.IFNα) were tested in murine models of lung cancer. Cytoreductive surgery was performed following treatment of advanced tumors. Mechanistic underpinnings were investigated using flow cytometry, in vivo leukocyte depletion methods and in vivo tumor neutralization assays.
AdV-tk and Ad.IFNα were effective in treating early lung cancers, but had little anti-tumor effects in late stage cancers. Interestingly, in late stage scenarios, surgical cytoreduction unmasked the anti-tumor potency of both immunotherapeutic approaches. Immune mechanisms that explained restoration in anti-tumor immune responses included increased CD8 T-cell trafficking and reduced myeloid derived suppressor cell populations.
This study demonstrates that surgical resection combined with immunotherapy may be a rational therapeutic option for patients with advanced stage cancer.
Journal of Hematology & Oncology 06/2012; 5:34. · 3.99 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Surgery is the most effective therapy for cancer in the United States, but disease still recurs in more than 40% of patients within 5 years after resection. Chemotherapy is given postoperatively to prevent relapses; however, this approach has had marginal success. After surgery, recurrent tumors depend on rapid neovascular proliferation to deliver nutrients and oxygen. Phosphatidylserine (PS) is exposed on the vascular endothelial cells in the tumor microenvironment but is notably absent on blood vessels in normal tissues. Thus, PS is an attractive target for cancer therapy after surgery. Syngeneic mice bearing TC1 lung cancer tumors were treated with mch1N11 (a novel mouse chimeric monoclonal antibody that targets PS), cisplatin (cis), or combination after surgery. Tumor relapses and disease progression were decreased 90% by combination therapy compared with a 50% response rate for cis alone (P = .02). Mice receiving postoperative mch1N11 had no wound-related complications or added systemic toxicity in comparison to control animals. Mechanistic studies demonstrated that the effects of mch1N11 were associated with a dense infiltration of inflammatory cells, particularly granulocytes. This strategy was independent of the adaptive immune system. Together, these data suggest that vascular-targeted strategies directed against exposed PS may be a powerful adjunct to postoperative chemotherapy in preventing relapses after cancer surgery.
Neoplasia (New York, N.Y.) 04/2012; 14(4):352-9. · 5.48 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Neutrophils play an established role in host defense and in killing invading microorganisms. Although neutrophils are traditionally considered in the context of their antibacterial functions, it is becoming increasingly clear that tumor-associated neutrophils (TAN) play a major role in cancer biology. Neutrophils make up a significant portion of the inflammatory cell infiltrate in many models of cancer. Like all other leukocytes, they move into tissues under the influence of specific chemokines, cytokines and cell adhesion molecules. The tumor microenvironment has been shown to be responsible for their recruitment in cancer. We have found that TAN are a distinct population of neutrophils, differing markedly in their transcriptomic profile from both naive neutrophils and the granulocytic fraction of myeloid-derived suppressor cells. Studies have demonstrated specific examples of tumor-mediated signals (such as transforming growth factor-β) that induce the formation of a pro-tumorigenic (N2) phenotype capable of supporting tumor growth and suppressing the antitumor immune response. However, there are also studies showing that TAN can also have an antitumorigenic (N1) phenotype. Herein, we explore the literature on the different mechanisms of TAN recruitment to tumors, the unique characteristics of TAN and what shapes their pro- and/or antitumor effects.
Carcinogenesis 03/2012; 33(5):949-55. · 5.70 Impact Factor
-
Julia Tchou,
Liang-Chuan Wang,
Ben Selven,
Hongtao Zhang,
Jose Conejo-Garcia,
Hossein Borghaei,
Michael Kalos,
Robert H Vondeheide, Steven M Albelda,
Carl H June,
Paul J Zhang
[show abstract]
[hide abstract]
ABSTRACT: Mesothelin is a cell-surface glycoprotein present on mesothelial cells and elicits T cell responses in a variety of cancers including pancreatic, biliary and ovarian cancer. Breast cancer is not known to express mesothelin. We postulated that mesothelin may be a unique tumor-associated antigen in triple negative breast cancer (TNBC), a less common breast cancer subtype which may have been under-represented in prior studies that characterized mesothelin expression. Therefore, we screened 99 primary breast cancer samples by immunohistochemistry analysis using formalin-fixed paraffin-embedded archival tumor tissues and confirmed that mesothelin was overexpressed in the majority of TNBC (67 %) but only rarely in <5 % ER(+) or Her2-neu(+) breast cancer, respectively. To determine whether mesothelin may be exploited as a novel immunotherapy target in breast cancer, an in vitro cell killing assay was performed to compare the ability of genetically modified T cells expressing a chimeric antibody receptor (CAR) specific for mesothelin (mesoCAR T cells) or non-transduced T cells to kill mesothelin-expressing primary breast cancer cells. A significantly higher anti-tumor cytotoxicity by mesoCAR T cells was observed (31.7 vs. 8.7 %, p < 0.001). Our results suggest that mesothelin has promise as a novel immunotherapy target for TNBC for which effective targeted therapy is lacking to date.
Breast Cancer Research and Treatment 03/2012; 133(2):799-804. · 4.43 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Prediction of cancer recurrence in patients with non-small cell lung cancer (NSCLC) currently relies on the assessment of clinical characteristics including age, tumor stage, and smoking history. A better prediction of early stage cancer patients with poorer survival and late stage patients with better survival is needed to design patient-tailored treatment protocols. We analyzed gene expression in RNA from peripheral blood mononuclear cells (PBMC) of NSCLC patients to identify signatures predictive of overall patient survival. We find that PBMC gene expression patterns from NSCLC patients, like patterns from tumors, have information predictive of patient outcomes. We identify and validate a 26 gene prognostic panel that is independent of clinical stage. Many additional prognostic genes are specific to myeloid cells and are more highly expressed in patients with shorter survival. We also observe that significant numbers of prognostic genes change expression levels in PBMC collected after tumor resection. These post-surgery gene expression profiles may provide a means to re-evaluate prognosis over time. These studies further suggest that patient outcomes are not solely determined by tumor gene expression profiles but can also be influenced by the immune response as reflected in peripheral immune cells.
PLoS ONE 01/2012; 7(3):e34392. · 4.09 Impact Factor
-
Zvi G Fridlender,
Jing Sun,
Inbal Mishalian,
Sunil Singhal,
Guanjun Cheng,
Veena Kapoor,
Wenhwai Horng,
Gil Fridlender,
Rachel Bayuh,
G Scott Worthen, Steven M Albelda
[show abstract]
[hide abstract]
ABSTRACT: The role of myeloid cells in supporting cancer growth is well established. Most work has focused on myeloid-derived suppressor cells (MDSC) that accumulate in tumor-bearing animals, but tumor-associated neutrophils (TAN) are also known to be capable of augmenting tumor growth. However, little is known about their evolution, phenotype, and relationship to naïve neutrophils (NN) and to the granulocytic fraction of MDSC (G-MDSC).In the current study, a transcriptomics approach was used in mice to compare these cell types. Our data show that the three populations of neutrophils are significantly different in their mRNA profiles with NN and G-MDSC being more closely related to each other than to TAN. Structural genes and genes related to cell-cytotoxicity (i.e. respiratory burst) were significantly down-regulated in TAN. In contrast, many immune-related genes and pathways, including genes related to the antigen presenting complex (e.g. all six MHC-II complex genes), and cytokines (e.g. TNF-α, IL-1-α/β), were up-regulated in G-MDSC, and further up-regulated in TAN. Thirteen of the 25 chemokines tested were markedly up-regulated in TAN compared to NN, including striking up-regulation of chemoattractants for T/B-cells, neutrophils and macrophages.This study characterizes different populations of neutrophils related to cancer, pointing out the major differences between TAN and the other neutrophil populations.
PLoS ONE 01/2012; 7(2):e31524. · 4.09 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Both advanced-stage lung cancer and malignant pleural mesothelioma are associated with a poor prognosis. Advances in treatment regimens for both diseases have had only a modest effect on their progressive course. Gene therapy for thoracic malignancies represents a novel therapeutic approach and has been evaluated in several clinical trials. Strategies have included induction of apoptosis, tumor suppressor gene replacement, suicide gene expression, cytokine-based therapy, various vaccination approaches, and adoptive transfer of modified immune cells. This review considers the clinical results, limitations, and future directions of gene therapy trials for thoracic malignancies.
Clinics in chest medicine 12/2011; 32(4):865-85. · 2.51 Impact Factor
-
Liang-Chuan S Wang,
Rachel C Lynn,
Guanjun Cheng,
Edward Alexander,
Veena Kapoor,
Edmund K Moon,
Jing Sun,
Zvi G Fridlender,
Stuart N Isaacs,
Stephen H Thorne, Steven M Albelda
[show abstract]
[hide abstract]
ABSTRACT: Since previous work using a nonreplicating adenovirus-expressing mouse interferon-β (Ad.mIFNβ) showed promising preclinical activity, we postulated that a vector-expressing IFNβ at high levels that could also replicate would be even more beneficial. Accordingly a replication competent, recombinant vaccinia viral vector-expressing mIFNβ (VV.mIFNβ) was tested. VV.mIFNβ-induced antitumor responses in two syngeneic mouse flank models of lung cancer. Although VV.mIFNβ had equivalent in vivo efficacy in both murine tumor models, the mechanisms of tumor killing were completely different. In LKRM2 tumors, viral replication was minimal and the tumor killing mechanism was due to activation of immune responses through induction of a local inflammatory response and production of antitumor CD8 T-cells. In contrast, in TC-1 tumors, the vector replicated well, induced an innate immune response, but antitumor activity was primarily due to a direct oncolytic effect. However, the VV.mIFNβ vector was able to augment the efficacy of an antitumor vaccine in the TC-1 tumor model in association with increased numbers of infiltrating CD8 T-cells. These data show the complex relationships between oncolytic viruses and the immune system which, if understood and harnessed correctly, could potentially be used to enhance the efficacy of immunotherapy.
Molecular Therapy 10/2011; 20(4):736-48. · 6.87 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Endocan is a proteoglycan expressed by endothelial cells in the lung that may inhibit leukocyte recruitment and thus prevent the development of acute lung injury (ALI). We tested the association of serum endocan levels with subsequent development of ALI after major trauma.
This was a single-center nested case-control study within a prospective cohort study of major trauma patients. Using an enzyme-linked immunosorbent assay test, we measured endocan levels from admission serum in 24 controls (no ALI) and 24 cases (ALI within 5 days of trauma). Multivariable logistic regression was used to test the association of admission serum endocan levels with subsequent ALI.
Patients who developed ALI had lower levels of endocan on admission (mean, 3.5 ± 1.4 ng/mL vs 4.9 ± 2.6 ng/mL in controls; P = .02). For each 1-unit increase in serum endocan level, the odds ratio for ALI development decreased (0.69; 95% confidence interval, 0.49-0.97; P = .03). Lower endocan levels remained associated with a higher incidence of ALI after adjustment for age and illness severity.
Lower levels of serum endocan on admission are associated with subsequent development of ALI in trauma patients. These observations may be explained by endocan-mediated blockade of leukocyte recruitment in the lung.
Journal of critical care 09/2011; 27(5):522.e11-7. · 2.13 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Clinical investigations have suggested that repression of the TGF-β type II receptor (TβRII) may be an important step in progression of lung adenocarcinoma from an indolent in situ state to a frank invasive carcinoma. To test this hypothesis, we compared the effects of deleting the murine homolog of this receptor (Tgfbr2) in a mouse model of mutant K-ras-induced lung carcinoma, which normally induces the formation of multifocal tumors of low invasive potential. In this model, loss of Tgfbr2 induced a highly invasive phenotype associated with lymph node metastasis and reduced survival. Tumor-associated stromal cells displayed an immunosuppressive profile marked by increased numbers of B and T cells. Moreover, tumor stromal cell profiling revealed a developmental TGF-β response profile that associated with a collagenized extracellular matrix and increased invasion of TGF-β nonresponsive tumor cells. Together, these results suggest that our KrasTgfbr2(-/-) mouse model of invasive lung carcinoma mirrors the genomic response and clinical progression of human lung adenocarcinoma, recapitulating changes in lung stromal pathways that occur in the tumor microenvironment during malignant progression in this disease.
Cancer Research 09/2011; 71(21):6665-75. · 7.86 Impact Factor
-
Gerhard Preissler,
Florian Loehe,
Ines V Huff,
Ulrich Ebersberger,
Vladimir V Shuvaev,
Iris Bittmann,
Iris Hermanns,
James C Kirkpatrick,
Karl Fischer,
Martin E Eichhorn,
Hauke Winter,
Karl W Jauch, Steven M Albelda,
Vladimir R Muzykantov,
Rainer Wiewrodt
[show abstract]
[hide abstract]
ABSTRACT: Donor organ shortage represents a major problem in lung transplantation. Donation after cardiac death could help to expand the pool of organs, but the additional period of warm ischemia after cardiac arrest aggravates primary graft dysfunction. The pulmonary endothelium of the graft constitutes an important source and target of reactive oxygen species generated during ischemia and reperfusion. Targeted protection of graft pulmonary endothelial cells by the antioxidant enzyme catalase, conjugated with a platelet/endothelial cell adhesion molecule-1 (PECAM-1) antibody to nanosized particles (anti-PECAM/catalase conjugates), might improve outcome in lung transplantation using donors after cardiac death and prolonged hypothermic preservation.
Left lung transplantation was performed in 18 pigs. Before cardiac arrest, donors received anti-PECAM/catalase, unconjugated component mixture or vehicle solution. After 90-min warm and 18-hr hypothermic ischemia, lungs were transplanted, and function was assessed during 6 hr after reperfusion. Samples of bronchoalveolar lavage fluid and lung tissue were taken thereafter. Six sham-operated animals served as controls.
During 6-hr reperfusion, anti-PECAM/catalase significantly ameliorated graft function, evidenced by major improvements of gas exchange and reduced intrapulmonary shunt fraction. Furthermore, lipid peroxidation, alveolar leakage, and edema formation were reduced in protected grafts. Similarly moderate lung pathology was seen after transplantation.
Augmentation of the antioxidant capacity of graft pulmonary endothelial cells with anti-PECAM/catalase nanoparticles represents a straightforward approach to enable a safe transplantation of prolonged preserved donation after cardiac death lungs. Anti-PECAM/catalase protection alleviated oxidative stress and allowed immediate reconstitution of normal gas exchange and pulmonary microcirculation, a prerequisite for improved graft and patient outcome.
Transplantation 08/2011; 92(4):380-7. · 4.00 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: To characterize the interactions of non-small cell lung cancer (NSCLC) tumors with the immune system at the level of mRNA and microRNA (miRNA) expression and to define expression signatures that characterize the presence of a malignant tumor versus a nonmalignant nodule.
We have examined the changes of both mRNA and miRNA expression levels in peripheral blood mononuclear cells (PBMC) between paired samples collected from NSCLC patients before and after tumor removal using Illumina gene expression arrays.
We found that malignant tumor removal significantly changes expression of more than 3,000 protein-coding genes, especially genes in pathways associated with suppression of the innate immune response, including natural killer cell signaling and apoptosis-associated ceramide signaling. Binding sites for the ETS domain transcription factors ELK1, ELK4, and SPI1 were enriched in promoter regions of genes upregulated in the presence of a tumor. Additional important regulators included five miRNAs expressed at significantly higher levels before tumor removal. Repressed protein-coding targets of those miRNAs included many transcription factors, several involved in immunologically important pathways. Although there was a significant overlap in the effects of malignant tumors and benign lung nodules on PBMC gene expression, we identified one gene panel which indicates a tumor or nodule presence and a second panel that can distinguish malignant from nonmalignant nodules.
A tumor presence in the lung influences mRNA and miRNA expression in PBMC and this influence is reversed by tumor removal. These results suggest that PBMC gene expression signatures could be used for lung cancer diagnosis.
Clinical Cancer Research 08/2011; 17(18):5867-77. · 7.74 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: The small molecule anti-tumor agent, 5,6-dimethylxanthenone-4-acetic acid (DMXAA, now called Vadimezan) is a potent macrophage and dendritic cell activating agent that, in the murine system, results in the release of large amounts of cytokines and chemokines. The mechanisms by which this release is mediated have not been fully elucidated. The mitogen-activated protein kinase (MAPK) pathways play an important role in the regulation of proinflammatory cytokines, such as TNF-α, IL-1β, as well as the responses to extracellular stimuli, such as lipopolysaccharide (LPS). The results of this study demonstrate that DMXAA activates three members of mitogen-activated protein kinase (MAPK) superfamily, namely p38 MAPK, extracellular signal-regulated kinases 1 and 2 (ERK1 and ERK2), and c-Jun N-terminal kinases (JNKs) via a RIP2-independent mechanism in murine macrophages. By using selective inhibitors of MAPKs, this study confirms that both activated p38/MK2 pathways and ERK1/2 MAPK play a significant role in regulation of both TNF-α and IL-6 protein production induced by DMXAA at the post-transcriptional level. Our findings also show that interferon-γ priming can dramatically augment TNF-α protein secretion induced by DMXAA through enhancing activation of multiple MAPK pathways at the post-transcriptional level. This study expands current knowledge on mechanisms of how DMXAA acts as a potent anti-tumor agent in murine system and also provides useful information for further study on the mechanism of action of this potential anti-tumor compound in human macrophages.
Biochemical pharmacology 07/2011; 82(9):1175-85. · 4.25 Impact Factor
-
Daniel H Sterman,
Andrew Haas,
Edmund Moon,
Adriana Recio,
Daniel Schwed,
Anil Vachani,
Sharyn I Katz,
Colin T Gillespie,
Guanjun Cheng,
Jing Sun,
Emmanouil Papasavvas,
Luis J Montaner,
Daniel F Heitjan,
Leslie Litzky,
Joseph Friedberg,
Melissa Culligan,
Carl H June,
Richard G Carroll, Steven M Albelda
[show abstract]
[hide abstract]
ABSTRACT: New therapeutic strategies are needed for malignant pleural mesothelioma (MPM). We conducted a single-center, open-label, nonrandomized, pilot and feasibility trial using two intrapleural doses of an adenoviral vector encoding human IFN-α (Ad.IFN-α2b). Nine subjects were enrolled at two dose levels. The first three subjects had very high pleural and systemic IFN-α concentrations resulting in severe "flu-like" symptoms necessitating dose de-escalation. The next six patients had reduced (but still significant) pleural and serum IFN-α levels, but with tolerable symptoms. Repeated vector administration appeared to prolong IFN-α expression levels. Anti-tumor humoral immune responses against mesothelioma cell lines were seen in seven of the eight subjects evaluated. No clinical responses were seen in the four subjects with advanced disease. However, evidence of disease stability or tumor regression was seen in the remaining five patients, including one dramatic example of partial tumor regression at sites not in contiguity with vector infusion. These data show that Ad.IFN-α2b has potential therapeutic benefit in MPM and that it generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor. Clinical trial registered with www.clinicaltrials.gov (NCT 01212367).
American Journal of Respiratory and Critical Care Medicine 06/2011; 184(12):1395-9. · 11.08 Impact Factor
-
[show abstract]
[hide abstract]
ABSTRACT: Mesothelioma represents an especially good target for gene therapy since few effective therapies exist, the disease remained relatively localized until late in its course, the tumor can be accessed relatively easily through the chest wall, and the thin layer of mesothelial cells offers a large surface area for efficient, rapid, and diffuse gene transfer. Gene therapy trials in mesothelioma have shown safety, and some limited evidence of efficacy. We present a review of clinical trials that have been performed in mesothelioma and describe several new approaches currently being pursued.
Current Treatment Options in Oncology 06/2011; 12(2):173-80. · 2.68 Impact Factor
