Barriers to therapy
CAR-T therapy has had impressive efficacy in hematological malignancies, but its efficacy in the treatment of solid tumors is limited by a number of mechanisms. Adapted from Srivastava and Riddell, Journal of Immunology. 2018 Jan; 200(2): 459-468.

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

MRI scans of lungs of KP mice treated with control T cells or ROR1 CAR-T cells. CAR-T cell-treated mice show heterogeneous responses, with some nodules regressing or showing stable growth, while other nodules progress rapidly. Unpublished data from Srivastava et al.

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 KrasLSL-G12D/+p53fl/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 trafficking of engineered T cells to solid tumors

2. Engineering T cells to resist the development of exhaustion

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