The antigen specificity of tumor-targeting T cells in non-small cell lung cancer

PROJECT SUMMARY This proposal outlines a five-year training program for Dr. Mark Lee, M.D., Ph.D., with the goal of preparing him for an independent academic research career as a physician-scientist. Dr. Lee completed doctoral studies in immunology at Harvard Medical School as part of the combined M.D./Ph.D. program, and is currently an

Instructor at the Brigham and Women’s Hospital and a board-certified Transfusion Medicine physician. Dr. Lee’s career development plan will build on his background in human immunology, adding didactic training and primary research experiences in computational oncology and cancer research. In this effort, Dr. Lee will be mentored by

Dr. Matthew Meyerson, who is an international leader in lung cancer genomics and has a history of mentoring physician-scientists who have transitioned to independent academic research positions, as well as a Scientific Advisory Committee composed of highly regarded physician-scientists (Dr. Eliezer Van Allen, Dr. Marcela Maus,

and Dr. David Barbie) who have expertise in computational oncology, cancer immunology, and cancer biology. The outstanding research environment and facilities available to Dr. Lee include laboratory space at both Dana- Farber Cancer Institute and the Broad Institute. In addition, using extensive career development resources within

the Harvard-affiliated hospital system, Dr. Lee will further develop critical career skills in scientific leadership, laboratory management, research communication, and grant writing. The long-term goal of the proposed research is to apply novel technologies to identify the targets of tumor-reactive T cells within cancer genomes,

in order to fundamentally understand immune responses in cancer patients and to therapeutically augment these responses. Although immunotherapy – and in particular, immune checkpoint blockade – has revolutionized treatment for select patients with non-small cell lung cancer (NSCLC), the majority of patients fail to respond.

Thus, increasing the efficacy of immunotherapy for non-responders remains a critical priority of cancer research. T cell-based therapies, including adoptive cellular therapies and T cell receptor (TCR) bispecific proteins, have led to major pathologic responses in cancer patients, including in non-responders to checkpoint blockade.

However, the currently limited set of well-defined tumor-reactive TCRs – and the technical difficulty of identifying tumor antigen/TCR pairs – currently restricts the number of NSCLC patients that can be treated with these novel therapies. Dr. Lee recently developed a high-throughput method that allows functional testing of thousands of

putative T cell targets, and will apply this method to identify the targets of T cell receptors in NSCLC patient tumor and blood specimens. Successful completion of this project will enable a more complete understanding of the cellular markers that enrich for tumor-reactive T cells (Aim 1) and a more complete understanding of how

tumor-reactive T cells in the peripheral blood respond to PD-1 blockade (Aim 2). Together with formal training, the proposed research will allow Dr. Lee to launch an independent career as an academic physician-scientist.