Treatment for patients with metastatic melanoma is inadequate. A subset of metastatic melanoma patients can undergo meaningful tumor regression in response to agents that modify lymphocyte activation and/or expansion, for example, IL-2, anti-CTLA4, or IL-2 in combination with transfer of ex vivo expanded tumor-infiltrating lymphocytes (TIL). However, most patients receiving these therapies fail to respond or to achieve lasting benefit. Preclinical studies conducted in our laboratories and confirmed by other investigators provide strong evidence that inhibition of TGF-beta signaling can markedly enhance the anti-tumor activity of CD8+ cytotoxic T-lymphocytes (CTL) in animal models. We propose to extend these studies to determine optimal approaches for clinical development of agents that inhibit TGF-beta signaling in combination with IL-2, IL-2 + TIL, anti-CTLA4, or other related immunotherapeutic manipulations. The goal of the clinical trials proposed in this application is to improve the rate and quality of tumor responses in patients with metastatic melanoma and to reduce the morbidity and mortality from this disease.
In Aim 1 we propose to confirm the improved anti-tumor effects of CD8+ TGFRII-DNR cells (CD8+ lymphocytes with the transgene for the dominant negative transforming growth factor beta receptor II) in mouse models and to determine if the anti-tumor activity of CD8+ TGFRII-DNR cells can be improved by addition of IL-2, addition of anti-CTLA4, and/or addition of anti-CD137. Furthermore, we propose to further characterize the mechanisms by which TGF-betaattenuates anti-tumor lymphocyte responses, in particular, to determine if the effects of TGF-beta are directly on CD8+ CTL or indirectly through induction of Treg (T regulatory cells which inhibit CD8+ and CD4+ anti-tumor lymphocyte responses), to determine the role of tumor driven TGF- beta in induction of Treg, and to determine whether and how Treg attenuate CD8+ CTL mediated tumor rejection.
In Aim 2, we propose to create a retroviral vector carrying the TGFRII-DNR gene suitable for use in human clinical trials, to develop methods for transduction and expansion of human melanoma-derived TIL, and to characterize the cell product. We will also use mouse melanoma models to determine the optimal conditions necessary to maximize the anti-tumor effects of TGFRII-DNR CTL, and will use the results of the experiments to guide the design of a clinical trial.
In Aim 3, we propose to evaluate non-genetic (pharmacologic) approaches to inhibit TGF-beta combined with an immunotherapy. Finally, in Aim 4, we propose to conduct proof of concept clinical trials in which TGF-beta inhibition is combined with an immune therapy. We propose that one of the clinical trials will involve adoptive transfer of melanoma TIL carrying the gene for TGFRII-DNR.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
5P50CA121974-05
Application #
8104129
Study Section
Special Emphasis Panel (ZCA1)
Project Start
Project End
Budget Start
2010-07-01
Budget End
2011-06-30
Support Year
5
Fiscal Year
2010
Total Cost
$256,461
Indirect Cost
Name
Yale University
Department
Type
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Sulkowski, Parker L; Scanlon, Susan E; Oeck, Sebastian et al. (2018) PTEN Regulates Nonhomologous End Joining By Epigenetic Induction of NHEJ1/XLF. Mol Cancer Res 16:1241-1254
Chen, Ling; Azuma, Takeshi; Yu, Weiwei et al. (2018) B7-H1 maintains the polyclonal T cell response by protecting dendritic cells from cytotoxic T lymphocyte destruction. Proc Natl Acad Sci U S A 115:3126-3131
Krauthammer, Michael (2018) Unraveling the etiology of primary malignant melanoma of the esophagus. J Thorac Dis 10:S1074-S1075
Das, Rituparna; Bar, Noffar; Ferreira, Michelle et al. (2018) Early B cell changes predict autoimmunity following combination immune checkpoint blockade. J Clin Invest 128:715-720
Ferrucci, Leah M; Cartmel, Brenda; Clare, Rachel A et al. (2018) Cross-sectional assessment of ultraviolet radiation-related behaviors among young people after a diagnosis of melanoma or basal cell carcinoma. J Am Acad Dermatol 79:149-152
Arbesman, Joshua; Ravichandran, Sairekha; Funchain, Pauline et al. (2018) Melanoma cases demonstrate increased carrier frequency of phenylketonuria/hyperphenylalanemia mutations. Pigment Cell Melanoma Res 31:529-533
Perry, Curtis J; Muñoz-Rojas, Andrés R; Meeth, Katrina M et al. (2018) Myeloid-targeted immunotherapies act in synergy to induce inflammation and antitumor immunity. J Exp Med 215:877-893
Liu, Xiaoni; Zhang, Shang-Min; McGeary, Meaghan K et al. (2018) KDM5B Promotes Drug Resistance by Regulating Melanoma Propagating Cell Subpopulations. Mol Cancer Ther :
Miller, Chad J; Muftuoglu, Yagmur; Turk, Benjamin E (2017) A high throughput assay to identify substrate-selective inhibitors of the ERK protein kinases. Biochem Pharmacol 142:39-45
Kluger, Harriet M; Zito, Christopher R; Turcu, Gabriela et al. (2017) PD-L1 Studies Across Tumor Types, Its Differential Expression and Predictive Value in Patients Treated with Immune Checkpoint Inhibitors. Clin Cancer Res 23:4270-4279

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