Personalized T Cell-Directed Cancer Immunotherapy

Endeavor Award (2023-Present)

Dana-Farber Cancer Institute: Catherine Wu, MD • The Broad Institute: Nir Hacohen, PhD; Fei Chen, PhD

Catherine Wu, MD

Nir Hacohen, PhD

Fei Chen, PhD

For over a decade, immune checkpoint blockade and cellular therapy for diverse cancer types have provided clear evidence of the transformative power of T cell-directed therapies. However, at the same time, better mechanistic understanding is urgently needed to improve the efficacy of these potentially life-saving therapies, as only a subset of patients will respond. Issues such as T cell exhaustion, insufficient understanding of neoantigen presentation and recognition, and an immunosuppressive tumor microenvironment all act as barriers for effective T cell anti-tumor response, particularly in solid tumors. To ensure T cell therapy is efficacious for more patients, there is a critical need to identify the critical tumor antigens and the receptors that detect them, and develop new methods to optimize the functionality of tumor-reactive T cells.

To achieve these goals, this Endeavor team has assembled a multidisciplinary group of investigators specializing in antigen discovery, spatial genomics, and T cell manipulation. The researchers plan to use samples from patients with colorectal cancer and high-grade serous ovarian cancer to investigate these questions. Their plan includes the identification of tumor-reactive T cell receptors (TCRs), the crucial TCRs for tumor killing, T cell clonotypes’ interactions with the tumor microenvironment (TME), and the optimal functional state of T cells for durable tumor control. They will integrate innovative methods that their groups have developed to achieve these goals. These include a scalable approach for rapid identification of tumor-reactive T cells and their target antigens; a spatial genomics technique called for sequencing TCRs, transcripts, and tumor DNA with spatial indexing; and methods to study factors controlling T cell state using perturbation coupled with single-cell and spatial transcriptomics.

The goal of this Endeavor team is to translate their findings into personalized and shared therapies by developing clinical trials that use T cells precisely engineered for optimal tumor control with genetic modulators and tumor-specific TCRs. By addressing the challenges in T cell therapy and understanding the roles of T cell states and the microenvironment, this research will contribute to more effective T-cell-directed cancer immunotherapies, potentially benefiting a broad range of malignancies and providing insights for precision T cell immunotherapy for cancer.