The goal of this translational project is to develop T cells modified to express chimeric antigen receptors (CAR T cells) as adoptive cellular therapy for patients with metastatic melanoma. We have shown in a pilot clinical trial in chronic lymphocytic leukemia that CAR T cells are capable of unprecedented on-target clinical activity. We now seek to develop new methods to safely test the antitumor CAR T cells against new target structures in patients with melanoma. This project brings together the skills of three laboratories and a team of clinical investigators to develop, implement, and test next generation CAR T cell strategies in melanoma. Our approach will use advanced engineering using mRNA vectors combined with optimized cell culture methods as our experimental platform. In preliminary work, we have (i) developed a new technology using electroporated T cells that express optimized mRNA CARs, and (ii) shown that CAR T cells targeting c-Met, a receptor tyrosine kinase markedly overexpressed in melanoma, have potent effects against c-Met+ tumor cells in vitro and in vivo. Because CAR expression in our mRNA system is transient, potentially toxic effects could be extinguished simply by discontinuing the administration of the engineered RNA CAR T cells. The ability to limit off-target exposure by discontinuing CAR administration with this new platform also creates the opportunity to rapidly test potent RNA CAR signaling domains for antitumor activity. We hypothesize that mRNA-based c-Met-specific engineered CAR T cells will allow us to optimize potency and safety in patients with metastatic melanoma and provide clinically meaningful tumor responses. Our proposal is therefore focused on testing this promising new approach with transiently expressed CARs, permitting a more rapid, cost-effective, and an intrinsically safer approach.
In Aim One, we will characterize expression and anti-melanoma effects of mRNA-based c-Met scFV engineered T cells in preclinical models.
In Aim Two, we will determine the clinical and immunological impact of administering autologous c-Met RNA CAR T cells in patients with metastatic melanoma in a phase I dose escalation clinical trial.

Public Health Relevance

This project aims to develop new immune therapy for patients with metastatic melanoma based on infusions of engineered T cells specific for the tumor. T cells engineered to express a chimeric antigen receptor specific for c-Met and encoded by mRNA will be optimized for potency in preclinical studies and then tested in a first-in-human dose escalation clinical trial for patients with metastatic melanoma.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
1P50CA174523-01A1
Application #
8664623
Study Section
Special Emphasis Panel (ZCA1-RPRB-7 (J1))
Project Start
Project End
Budget Start
2014-09-15
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$296,514
Indirect Cost
$21,250
Name
Wistar Institute
Department
Type
DUNS #
075524595
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kaur, Amanpreet; Webster, Marie R; Marchbank, Katie et al. (2016) sFRP2 in the aged microenvironment drives melanoma metastasis and therapy resistance. Nature 532:250-4
Lu, Hezhe; Liu, Shujing; Zhang, Gao et al. (2016) Oncogenic BRAF-Mediated Melanoma Cell Invasion. Cell Rep 15:2012-24
Amaravadi, Ravi; Kimmelman, Alec C; White, Eileen (2016) Recent insights into the function of autophagy in cancer. Genes Dev 30:1913-30
Fatkhutdinov, Nail; Sproesser, Katrin; Krepler, Clemens et al. (2016) Targeting RRM2 and Mutant BRAF Is a Novel Combinatorial Strategy for Melanoma. Mol Cancer Res 14:767-75
Kumar, Vinit; Cheng, Pingyan; Condamine, Thomas et al. (2016) CD45 Phosphatase Inhibits STAT3 Transcription Factor Activity in Myeloid Cells and Promotes Tumor-Associated Macrophage Differentiation. Immunity 44:303-15
Shannan, Batool; Chen, Quan; Watters, Andrea et al. (2016) Enhancing the evaluation of PI3K inhibitors through 3D melanoma models. Pigment Cell Melanoma Res 29:317-28
Gimotty, Phyllis A; Shore, Ronald; Lozon, Nancy L et al. (2016) Miscoding of Melanoma Thickness in SEER: Research and Clinical Implications. J Invest Dermatol 136:2168-2172
Natale, Christopher A; Duperret, Elizabeth K; Zhang, Junqian et al. (2016) Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors. Elife 5:
Krepler, Clemens; Xiao, Min; Sproesser, Katrin et al. (2016) Personalized Preclinical Trials in BRAF Inhibitor-Resistant Patient-Derived Xenograft Models Identify Second-Line Combination Therapies. Clin Cancer Res 22:1592-602
Wang, Joshua X; Fukunaga-Kalabis, Mizuho; Herlyn, Meenhard (2016) Crosstalk in skin: melanocytes, keratinocytes, stem cells, and melanoma. J Cell Commun Signal 10:191-196

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