Immune checkpoint inhibitors like ipilimumab (anti-CTLA4) and nivolumab (anti-PD1) are revolutionizing cancer treatment. Understanding the genetic basis of response and resistance to immune checkpoint inhibitors are critical for improving outcomes with current agents and for developing new ones. Patients can undergo dramatic remissions after treatment while others reap no benefit. Furthermore, the immune phenotype shows substantial temperospatial variability and is influenced by multiple variables. The rationale of this project is that there is a fundamental genetic basis underlying response to immune checkpoint inhibitors that is poorly understood. Our preliminary data demonstrates that response to immune checkpoint blockade is strongly determined by the tumor mutation landscape and dictated by a specific neoantigen repertoire. We will apply a conceptually and technically innovative, systematic, multidisciplinary, and highly collaborative approach to elucidate the neoantigen landscape underlying response to immune checkpoint inhibitors. Our contribution here is expected to provide unparalleled mechanistic detail on how immune checkpoint inhibitors function and to provide biomarkers to identify patients who will benefit from PD-1 blockade. Furthermore, building on data showing that resistance may be mediated by immune pressure and immunoediting, we will shed light into how resistance to these drugs develop, providing definitive evidence for causal mechanisms of anti-tumor immunity. 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 much needed precise biomarkers, and establish a foundation to develop more effective immunotherapy.
Lung cancer is the most common cancer and leading cause of cancer related death worldwide, accounting for more than 1.6 million cases and 1.3 million deaths annually. The recent approvals of immune checkpoint inhibitors, nivolumab and pembrolizumab, for the treatment of non-small cell lung cancer have represented a major step forward, however little is understood as to (1) how adaptive immune resistance occurs within the tumor, (2), why only a small subset of patients respond to anti-PD-1 and (3) what are the T cells targeting at a genetic level. The leading hypothesis is that the mutation landscape is important with data now emerging from our group and others, demonstrating the mutation load is important in immune checkpoint blockade response however this needs to be studied more exhaustively. This proposal will apply new technologies to the study of response and resistance to immunotherapies in the context of a multi-disciplinary team with expertise in patient-oriented research and immune monitoring, comprehensive genetics and informatics analysis of the tumor microenvironment with state of the art validation in vitro and mouse modeling. The goals of this project are broadly to perform a deep characterization of the genetics of responders and non-responders to immune checkpoint blockade in NSCLC.
