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.
|Sarvi, Sana; Crispin, Richard; Lu, Yuting et al. (2018) ALDH1 Bio-activates Nifuroxazide to Eradicate ALDHHigh Melanoma-Initiating Cells. Cell Chem Biol 25:1456-1469.e6|
|Noguera-Ortega, Estela; Amaravadi, Ravi K (2018) Autophagy in the Tumor or in the Host: Which Plays a Greater Supportive Role? Cancer Discov 8:266-268|
|Jenkins, Russell W; Aref, Amir R; Lizotte, Patrick H et al. (2018) Ex Vivo Profiling of PD-1 Blockade Using Organotypic Tumor Spheroids. Cancer Discov 8:196-215|
|Gangadhar, Tara C; Savitch, Samantha L; Yee, Stephanie S et al. (2018) Feasibility of monitoring advanced melanoma patients using cell-free DNA from plasma. Pigment Cell Melanoma Res 31:73-81|
|Zhang, Gao; Wu, Lawrence W; Mender, Ilgen et al. (2018) Induction of Telomere Dysfunction Prolongs Disease Control of Therapy-Resistant Melanoma. Clin Cancer Res 24:4771-4784|
|Natale, Christopher A; Li, Jinyang; Zhang, Junqian et al. (2018) Activation of G protein-coupled estrogen receptor signaling inhibits melanoma and improves response to immune checkpoint blockade. Elife 7:|
|Hu, Xiaowen; Sood, Anil K; Dang, Chi V et al. (2018) The role of long noncoding RNAs in cancer: the dark matter matters. Curr Opin Genet Dev 48:8-15|
|Liu, Shujing; Zhang, Gao; Guo, Jianping et al. (2018) Loss of Phd2 cooperates with BRAFV600E to drive melanomagenesis. Nat Commun 9:5426|
|Reyes-Uribe, Patricia; Adrianzen-Ruesta, Maria Paz; Deng, Zhong et al. (2018) Exploiting TERT dependency as a therapeutic strategy for NRAS-mutant melanoma. Oncogene 37:4058-4072|
|Yam, Clinton; Xu, Xiaowei; Davies, Michael A et al. (2018) A Multicenter Phase I Study Evaluating Dual PI3K and BRAF Inhibition with PX-866 and Vemurafenib in Patients with Advanced BRAF V600-Mutant Solid Tumors. Clin Cancer Res 24:22-32|
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