Immunotherapy using CAR-T cells has shown impressive efficacy in B cell malignancies but has largely been ineffective when targeting antigens on epithelial cancers, which account for 80-90 percent of all cancers. The Srivastava lab is focused on using clinically relevant animal models of human cancers to define the mechanisms limiting the activity of CAR- and TCR-engineered T cells in solid tumors and to evaluate strategies to overcome these barriers. A major focus of the lab is in understanding the principles that govern basic T cell trafficking, persistence, and activity and applying these principles to engineer more effective adoptive T cell therapies for human cancers. Our long-term goal is to work with clinical colleagues and industry partners to translate the most promising strategies to the clinic.

Developing genetically-engineered mouse models to study CAR-T cell therapy for solid tumors

Transplantable and tumor xenograft models lack clinically relevant tumor microenvironments (TME), making it difficult to study the mechanisms that limit activity of transferred T cells in solid tumors. We recently adapted the Kras^LSL-G12D/+p53^fl/fl (KP) genetically engineered mouse (GEM) model of non-small cell lung cancer, which mimics the initiation, progression, and immunosuppressive TME of human lung cancer, to express a target for CAR-T cells, and demonstrated that this model mirrors many of the barriers to effective CAR-T cell therapy observed in patients, including poor CAR-T cell infiltration into tumors and acquired dysfunction. Using this model, we identified a novel lymphodepletion regimen that induces immunogenic tumor cell death and activates tumor macrophages to express T cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the TME, and increased tumor sensitivity to anti-PD-L1 checkpoint blockade and improved survival. However, the infiltrating CAR-T cells still became dysfunctional over time, suggesting that additional strategies to recruit greater numbers of T cells that retain function are needed to achieve durable efficacy. Current research in the lab is focused on:

1. Improving infiltration of engineered T cells into solid tumor masses

2. Engineering T cells to resist the development of exhaustion

3. Preserving the function of engineered T cells in immunosuppressive tumor microenvironments