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.
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.
|Kaur, Amanpreet; Ecker, Brett L; Douglass, Stephen M et al. (2018) Remodeling of the Collagen Matrix in Aging Skin Promotes Melanoma Metastasis and Affects Immune Cell Motility. Cancer Discov :|
|Chen, Gang; Huang, Alexander C; Zhang, Wei et al. (2018) Exosomal PD-L1 contributes to immunosuppression and is associated with anti-PD-1 response. Nature 560:382-386|
|Torre, Eduardo; Dueck, Hannah; Shaffer, Sydney et al. (2018) Rare Cell Detection by Single-Cell RNA Sequencing as Guided by Single-Molecule RNA FISH. Cell Syst 6:171-179.e5|
|Duperret, Elizabeth K; Trautz, Aspen; Stoltz, Regina et al. (2018) Synthetic DNA-Encoded Monoclonal Antibody Delivery of Anti-CTLA-4 Antibodies Induces Tumor Shrinkage In Vivo. Cancer Res 78:6363-6370|
|Kugel 3rd, Curtis H; Douglass, Stephen M; Webster, Marie R et al. (2018) Age Correlates with Response to Anti-PD1, Reflecting Age-Related Differences in Intratumoral Effector and Regulatory T-Cell Populations. Clin Cancer Res 24:5347-5356|
|Nicastri, Michael C; Rebecca, Vito W; Amaravadi, Ravi K et al. (2018) Dimeric quinacrines as chemical tools to identify PPT1, a new regulator of autophagy in cancer cells. Mol Cell Oncol 5:e1395504|
|Duperret, Elizabeth K; Wise, Megan C; Trautz, Aspen et al. (2018) Synergy of Immune Checkpoint Blockade with a Novel Synthetic Consensus DNA Vaccine Targeting TERT. Mol Ther 26:435-445|
|Yuan, Jiao; Hu, Zhongyi; Mahal, Brandon A et al. (2018) Integrated Analysis of Genetic Ancestry and Genomic Alterations across Cancers. Cancer Cell 34:549-560.e9|
|Onorati, Angelique V; Dyczynski, Matheus; Ojha, Rani et al. (2018) Targeting autophagy in cancer. Cancer 124:3307-3318|
|Perego, M; Maurer, M; Wang, J X et al. (2018) A slow-cycling subpopulation of melanoma cells with highly invasive properties. Oncogene 37:302-312|
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