My goal in applying for the Lung Cancer Foundation of America/Bristol-Myers-Squibb/International Lung Cancer Foundation Young Investigator Research Grant in Translational Immuno-oncology is to progress towards becoming an independent investigator in the field of translational lung cancer immunology. I began my research career as a medicinal chemist. I obtained my doctoral research training, as a combined MD/PhD student, in the laboratory of Dr. Michael Jung in the Department of Chemistry at UCLA. My research focused on the total synthesis of two natural products, auripyrone A and B, which possess potent cytotoxicity against cervical cancer.
My thesis project culminated in multiple publications, including one in the prestigious chemistry journal Angewandte Chemie. After medical school, I obtained my Internal Medicine, and Pulmonary and Critical Care training at UCLA with a specialty in lung cancer. Currently, I am an Assistant Professor in the Division of Pulmonary and Critical Care Medicine at UCLA and the VA Greater Los Angeles Healthcare System. My research efforts aim to enhance our understanding of the immunopathogenesis of lung cancer and improve immunotherapeutic strategies.
Lung cancer remains the leading cause of cancer death in the United States with approximately 85% of patients having non-small cell lung cancer (NSCLC). Although immunotherapy has revolutionized the treatment landscape of NSCLC, durable responses are limited to only a subset of patients. Therefore, there is a critical need for the development of novel strategies that can enhance the efficacy of immune checkpoint inhibitors (ICIs) in NSCLC. My post-doctoral research under the mentorship of Dr. Dubinett has focused on developing immune-based strategies, including chemokine gene-modified dendritic cell (DC)-based in situ vaccination, to improve the effectiveness of ICI in NSCLC.
A key hurdle in the advancement of immunotherapies in NSCLC is the lack of immunogenic preclinical models. I have recently developed novel murine models of NSCLC that possess the common driver mutations and increased tumor mutational burden (TMB) which recapitulate the mutational landscape and therapeutic vulnerabilities of human disease. The manuscript was published in Cancer Immunology Immunotherapy this year. This platform has resulted in multiple informative preclinical trials in our laboratory.
In a recent co-first author publication in Cancer Research, in collaboration with a graduate student, we demonstrated that myeloid-derived suppressive cells (MDSC) mediate resistance to ICIs in LKB1-deficient NSCLCs, and that inhibition of MDSCs can sensitize LKB1-deficient tumors to ICIs. These findings are of significant clinical importance given that loss of LKB1 is the primary genomic driver of resistance to ICI in human NSCLC.
Utilizing our novel murine models of NSCLC, we have shown that in situ vaccination with Ccl21 gene-modified DCs (CCL21-DC) potentiates the anti-PD-1 efficacy. Immunophenotyping studies with flow cytometry and scRNA-seq of the TME revealed that combination therapy reprogrammed the myeloid compartment to be less immunosuppressive, and induced T cell infiltration, Th1 polarization, as well as the enrichment of stem-like T cells within the TME. Notably, combination therapy resulted in immunoediting of tumor sub-clones and the generation of systemic tumor-specific immunity in a subset of mice that were cured of disease.
In an ongoing phase 1 trial combining IT CCL21-DC with anti-PD-1 pembrolizumab in patients with advanced stage NSCLC, we are currently evaluating the safety and efficacy of combination therapy. I serve as a member of the immune-monitoring team for this trial. My current proposal, “’Longitudinal assessment of tumor antigen profiles and T cell repertoires in advanced NSCLC patients treated with CCL21-DC in situ vaccination combined with pembrolizumab,” seeks to enhance our understanding of the critical immune mediators of response to the combination therapy in NSCLC. Then we will evaluate the hypothesis that in situ vaccination with CCL21-DC in combination with anti-PD-1 could expand the repertoire of tumor-specific T cells and generate systemic tumor-specific T cell responses that result in tumor immunoediting.
The Lung Cancer Foundation of America/Bristol-Myers Squibb/International Lung Cancer Foundation Young Investigator Research Grant in Translational Immuno-oncology will provide invaluable support and facilitate the establishment of my independent research program under the guidance of my mentor committee.
Anti-PD-1 immunotherapy improves the capacity of a patient’s T cells to eliminate lung cancer cells. However, anti-PD-1 immunotherapy does not work in many patients with ‘cold tumors’ that lack T cell infiltration prior to initiation of therapy. To combat this problem, we have developed a tumor vaccination approach, where we directly inject antigen-presenting dendritic cells that are derived from the same patient and modified to secrete a molecule called CCL21 (CCL21-DC) into lung tumors.
We have shown that vaccination with CCL21-DC activates host T cells against the tumor and promotes infiltration of T cells into the tumor, turning ‘cold tumors’ into ‘hot tumors.’ In mouse models, we observed that tumor vaccination with CCL21-DC sensitizes resistant lung cancers to anti-PD-1 therapy. We are currently testing this combination approach in a phase I clinical trial in late-stage lung cancer patients who have failed anti-PD-1 or other targeted therapies and do not have effective treatment options.
One benefit of tumor vaccination is that DCs can potentially generate broad T cell responses against diverse tumor antigens (abnormal tumor proteins that are targets of T cells). This, in turn, can result in robust T cell responses that effectively eliminate tumor cells. Our preliminary data in mice support this hypothesis.
In this proposal we seek to validate this hypothesis using patient samples from our clinical trial and improve our understanding of the changes in tumor antigens and host T cells after therapy. These studies could facilitate the development of novel immunotherapeutic strategies in lung cancer.