Susan Kaech, PhD
Director and Professor, NOMIS Center for Immunobiology and Microbial Pathogenesis
Salk Institute for Biological Studies
Steve Schoenberger, PhD
Center Head and Professor, Division of Developmental Immunology
La Jolla Institute for Immunology
Sandip Patel, MD
Associate Professor and Co-Leader of Experimental Therapeutics
Moores Cancer Center
University of California, San Diego Health
The goal of this project is to increase our understanding of the immunologic mechanisms that influence the response to immune checkpoint blockade. The project will use an unbiased neoantigen discovery platform to screen for neoantigen-specific T cells and compare the quantity and quality (i.e. breadth, diversity and neo-antigen affinity for MHC) of these neoantigen-specific T cells in patients who are (1) exceptional responders (2) non-responders and (3) progressors. The results from this study will help predict which patients respond to immunotherapy, and could lead to the development of new therapies that increase the efficacy of current immunotherapies.
Immune checkpoint inhibitors have dramatically changed the landscape of medical oncology over the past 5 years. Anti-PD-1 antibodies such as pembrolizumab and nivolumab are now FDA-approved as first-line therapies for unresectable or metastatic melanoma, adjuvant treatment with lymph node involvement after complete resection of melanoma, and as first-line treatment of patients with Stage III NSCLC who are not candidates for surgical resection or definitive chemoRT or patients with metastatic NSCLC who progress after chemotherapy. However, immune checkpoint inhibitors only elicit a response in about 20-25% of patients. The majority of patients do not respond (are non-responders), or they initially respond to immune checkpoint therapy and then their tumor develops resistance (progressors). Very few patients are ‘exceptional responders’ who demonstrate a complete response for an extended period of time.
The holy grail of the field is to determine why some patients respond to immune checkpoint blockade and others do not. Expression of PD-L1 and the density of tumor-infiltrating CD8+ T cells have not been reproducible as reliable biomarkers of response. While several studies have reported that higher tumor mutational burden correlates with better clinical outcomes, these studies do not consider which of these mutations actually induce anti-tumor immunity. The field is lacking an in-depth analysis of how the quality and quantity of tumor-reactive T cells correlates with clinical outcomes after immune checkpoint inhibition. No one has systematically characterized neoantigen-specific T cell-mediated responses to immunotherapy in exceptional responders, non-responders and progressors in order to better predict who will respond.
Neoantigens are absent from the germline genome but arise in tumors as a result of somatic mutation. Each neoantigen represents a unique target for CD4+ and CD8+ T cells that is specific to the tumor, allowing the adaptive immune system to direct its response against the tumor while sparing normal tissue.
Using a neoantigen discovery workflow pioneered by Steve Schoenberger, PhD (La Jolla Institute for Immunology), the team of Susan Kaech, PhD (Salk Institute), Sandip Patel, MD (UCSD), and Dr. Schoenberger will compare T cell responses in ‘exceptional responders,’ ‘progressors’ and ‘non-responders.’ After using whole exome sequencing of tumors to discover mutations, they will use RNA sequencing to determine which mutations are translated into antigenic peptides and are tumor-specific. Next, they will generate a synthetic peptide library to these neoantigens and screen them for immunogenicity using ELISPOT and flow cytometry. They will sequence the TCR of neoantigen-specific T cells to identify T cell clones that can be tracked over time. The investigators have access to a time-series of blood samples collected from more than 60 patients with metastatic lung cancer who received pembrolizumab and vary in their responses to treatment. Primers will be used to do TCR sequencing of cryopreserved T cells from these patients to characterize the anti-tumor T cell response in patients with different outcomes. This study will help determine whether exceptional responders to immune checkpoint inhibition have T cell responses that are larger and longer-lasting than those of non-responders or progressors, or whether they are more diverse and encompass a larger breadth of neoantigens.
By analyzing the kinetics, magnitude and breadth of the neoantigen-specific T cells in patients receiving immunotherapy, this project aims to increase our understanding of neoantigen-specific T cell responses in patients with exceptional response vs. no response vs. progression. In the future, the neoantigen discovery platform used in this study could be used as a clinical diagnostic to predict which patients will respond to immunotherapy. By identifying common neoantigens in patients who are exceptional responders, these neoantigens could serve as targets for new therapies that augment the efficacy of immune checkpoint blockade.