Engineering of Tumor-Selective CAR for Adoptive Cell Therapy Against Kidney Cancer
Abstract
According to the National Cancer Institute, kidney cancer accounts for 3% of all cancer cases and 2% of all cancer death in the United States. Although small molecular drug therapies that target oncogenic molecular and genetic changes in cells have significantly prolonged the survival of patients with advanced renal cell carcinoma (RCC), the most deadly form of kidney cancer, treatment eventually fails for most patients due to acquired drug resistance. Great clinical responses have been observed for the new generation of targeted immunotherapies aimed at arming the patients’ own immune system to fight cancer by blocking certain proteins responsible for suppressing immune cells from killing cancer cells, but only a small fraction of RCC patients show objective control of tumor growth after treatment, and complete tumor regression is rarely seen. Autologous transplantation of T cells engineered to harbor an artificial receptor called chimeric antigen receptor (CAR) can directly arm patients with tumor-killing immune cells. One such CAR therapy was able to mediate killing of tumor cells in a Phase I clinical trial, but significant adverse effects were observed, owing to “off-tumor” killing of normal tissue cells expressing the target protein that the CARs recognized. Our laboratory uncovered a novel and effective way to mitigate this toxicity problem by masking the CAR with a switchable peptide. The masking peptide keeps CARs from killing healthy cells in the normal tissue environment, whereas in the tumor environment, the peptide blockade is removed by proteases produced by cells in the tumor mass, thereby unleashing the full function of the CAR-harboring T (CAR-T) cells to kill cancer cells. Thus, this masked CAR therapy becomes more tumor-selective and safer. In addition, our research team discovered a method to endow CAR-T cells with the capacity to make molecular species to overcome one of cancer’s main defenses against immunotherapy. This “armored” CAR therapy was found to be remarkably potent in a mouse model of human lung cancer. In this application, we propose a series of experiments, ranging from cell engineering to human tumor models in mice, to demonstrate the feasibility and effectiveness of this masked and/or armored CAR therapy for treating RCC. If successful, data from this study can be used to support the future planning of clinical trials. This grant covers two of the Fiscal Year 2016 (FY16) Peer Reviewed Cancer Research Program (PRCRP) Topic Areas, Immunotherapy and Kidney Cancer. Because Veterans who participated in radiation-risk activities are at higher risk for kidney cancer, this proposed study also directly addresses the FY16 PRCRP Military Relevance Focus Areas and potentially offers an advanced T cell transplantation therapy that is safer and more effective so that more military Service members, Veterans, and their beneficiaries with kidney cancer can benefit from such a treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710474
Entities
People
- Pin Wang
Organizations
- United States Army
- University of Southern California