Human Oncology and Pathogenesis Program
Memorial Sloan Kettering Cancer Center
Our research focuses on cancer genomics. We use large-scale approaches to solve clinically pressing questions in cancer research. Specifically, we are interested in characterizing the molecular determinants of response to cancer therapeutics.
Our ultimate goal is to develop new, more effective diagnostic and therapeutic modalities for cancer patients. Our innovative work is providing fundamental insights into questions such as 1) what dictates immunotherapy efficacy and 2) what drives cancer aggressiveness.
Timothy A. Chan MD, PhD is a cancer geneticist and radiation oncologist at the Memorial Sloan Kettering Cancer Center. He is the principal investigator of a cancer genetics laboratory in the Human Oncology and Pathogenesis Program and an Attending Physician in the Dept. of Radiation Oncology. Dr. Chan grew up in Southern California and attended Harvard College for his undergraduate work. He then completed an MD, PhD, residency, and post-doctoral fellowship at the Johns Hopkins School of Medicine. In 2007, he joined the faculty of the Memorial Sloan Kettering Cancer Center.
Dissecting efficacy and resistance to immune checkpoint blockade therapy
Immunotherapy is revolutionizing cancer therapy. New agents that act by blocking immune checkpoints have demonstrated activity in a variety of human cancers. These agents activate a patient’s immune cells so they can attack cancers. For example, ipilimumab (anti-CTLA4 antibody) and pembrolizumab (anti-PD1 antibody) have both shown significant benefit in clinical trials. In patients with advanced melanoma or lung cancer, treatment with these agents has resulted in dramatic responses and remissions. However, the molecular determinants of response are unknown.
“The Pershing Square Sohn Prize will allow me to pursue high risk, high reward work in the field of immunotherapy and immunogenomics. This award provides not only the resources but the environment and relationships that will accelerate the work and help prepare our findings for use in the clinic. ”
In this proposal, we will work towards characterizing the factors which determine whether patients respond to immune checkpoint blockade therapy or are resistant. Furthermore, we will determine why resistance to the treatment develops. Our preliminary data suggests that a tumor’s mutational profile is the major factor driving response. We have discovered that tumor mutations create new peptides that the immune system sees as foreign (neoantigens). The presence of specific combinations of these new peptides are needed for the immune checkpoint inhibitors to optimally activate an immunologic anti-tumor response. Our work here will comprehensively define the neoantigens required for response and refine these findings for use in the clinic. Moreover, we will elucidate how changes in these neoantigens underlie acquired resistance to immunotherapy. Should our work succeed, we envision substantial utility for similar studies for other cancers. Such an understanding will provide great insight into the mechanisms underlying how immune checkpoint blockade works, provide sorely needed biomarkers, and establish a foundation to develop more effective immunotherapy.
“To me, innovation means “thinking outside the box.” It means pursuing concepts that are not simply evolutionary but reflect novel approaches or a convergence and synthesis of previously unrelated lines of investigation.”