A Lung Cancer Vaccine? Ask Dr. Salehi-Rad
As a recipient of the LCFA Young Investigator Research Grant in Translational Immuno-oncology, Dr. Ramin Salehi-Rad’s goal is to progress toward becoming an independent investigator in the field of translational lung cancer immunology. Translational research is aimed at converting immunology laboratory research results into results that directly benefit humans. Immunotherapy has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC).
However, lasting, permanent, and stable responses to NSCLC immunology treatments are limited to a small group of patients. As such, Dr. Salehi-Rad recognizes the critical need for the development of new strategies where these immunotherapy drugs can do what they are supposed to for more lung cancer cases. Perhaps a lung cancer vaccine?
Aiming for UCLA Early On
When Dr, Ramin Salehi-Rad was sixteen years old, he and his family immigrated to the United States from war-torn Iran. Despite being a high school student at the time, he has his sights set on attending UCLA. Ramin was always interested in science and began his college career focusing on chemistry. Once he was exposed to medicine, though, he switched gears.
“My family emigrated to Ventura, California because it was the only place we had any family. our only family. We moved to the United States with a specific goal: the opportunity to attend Universities in America. I knew nothing about US colleges and only knew about UCLA because my cousin had gone there.”
A Lung Cancer Vaccine – One Young Investigator’s Dream
Today, Dr. Salehi-Rad is a lung cancer researcher studying the effects of a novel lung cancer vaccine that uses modified cells from the patient’s own tumor. The effect sensitizes resistant lung cancers to current anti-PD-1 immunotherapies. Through the LCFA Young Investigator grant, Dr. Salehi-Rad hopes to facilitate the development of novel immunotherapeutic strategies to treat lung cancer.
From Chemistry to Oncology
Dr. Ramin Salehi-Rad began his research career as a medicinal chemist. Using a range of chemistry techniques, synthetic organic chemistry, and data analysis tools, medicinal chemists design and create new medicines to combat a particular disease or condition.
As an undergraduate student at the University of California Los Angeles (UCLA), he conducted research for three years in the laboratory of Robert Armstrong, Ph.D., where he was afforded the opportunity to collaborate with a graduate student on the synthesis of a library of opioid analogs utilizing a solid-phase combinatorial approach. After the departure of the graduate student, Dr. Salehi-Rad independently synthesized and characterized over 100 opioid analogs to complete the project. This research experience confirmed his desire to become a physician-scientist.
From Researcher to MD/PhD
After pursuing a combined MD/Ph.D. degree at UCLA, sponsored by the Medical Scientist Training Program (MSTP), he obtained his doctoral research training in the laboratory of Michael Jung, Ph.D., in the Department of Chemistry and Biochemistry at UCLA. As a doctoral student, Dr. Salehi-Rad was the recipient of the competitive NIH Chemistry and Biology Interface award. His research focused on the total synthesis of two natural products against cervical cancer.
Dr. Salehi-Rad’s thesis project culminated in multiple peer-reviewed publications, including a manuscript in the Journal of the American Chemical Society. Salehi-Rad credits research experience with the intellectual independence that is necessary for conducting a rigorous scientific investigation. Following medical school, Dr. Salehi-Rad completed a residency in internal medicine as well as a fellowship in pulmonary and critical care. He knew that he wanted to be in cancer research and became interested in lung cancer immunology/immunotherapy as a pulmonary fellow so naturally, Dr. Dubinett was a perfect fit for him as a mentor, “given his expertise in immunology and lung cancer and his extensive track record as a mentor and MOST importantly how kind and supportive he is,” says Dr. Salehi-Rad.
Lots of Research With Some LA Sports Trivia
Dr. Ramin Salehi-Rad is a pulmonologist in Los Angeles, California, and is affiliated with UCLA Medical Center. When he is not busy doing his work as a physician, Dr. Salehi-Rad can be found rooting for both the LA Lakers and the Dodgers. A note-worthy trivia fact: When beloved and iconic Los Angeles sports commentator Ross Porter suffered from a cardiac arrest, Dr. Salehi-Rad was the overnight physician who, along with several colleagues, successfully revived him. You can read more about it here.
Dr. Salehi-Rad joins an impressive group of Young Investigators funded through the LCFA/ILCF research grants that have helped direct more than $8 million toward lung cancer research in order to attract the best and the brightest to the field of lung cancer. The goal is to fund the best research to make the largest possible positive impact on patients with lung cancer.
Young Investigator Research Grant in Translational Immuno-oncology
About the LCFA-Funded Research
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.
Longitudinal assessment of tumor antigen profiles and T cell repertoires in advanced NSCLC patients treated with CCL21-DC in situ vaccination combined with pembrolizumab
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 for lung cancer.