ASCI / Young Physician-Scientist Awards, 2024

Sneha Ramakrishna, MD focuses her research on identifying mechanisms of chimeric antigen receptor T cell (CAR-T) failure in patients using multi-dimensional analyses of patient samples and developing approaches to optimize CAR-T therapies for future patients. Over the last decade, she has curated skills to develop and assess CAR-T therapies in the lab, care for patients receiving CAR-T therapies in the clinic, and interrogate the mechanisms of CAR-T failure following treatment back at the bench. Her focus on reverse translation – the connection of the bedside back to the bench – began in fellowship, where her work demonstrated that tumor antigen expression directly affects patient CAR-T expansion, memory development, and persistence, and identified that drug-mediated antigen upregulation could enhance CAR-T activity and reduce relapse risk. After fellowship, she came to Stanford, where she now leads an interdisciplinary team that designs, develops, and implements a robust correlative science platform into our novel CAR-T trials. Harnessing single-cell multi-dimensional analyses, their research aims to understand the molecular signatures of successful and failed CAR-Ts in their patients. Analyzing patient samples from their GD2 CAR-T diffuse midline glioma trial, they identified that intracerebroventricular CAR-T administration correlates with enhanced pro-inflammatory cytokines and reduced immunosuppressive cell populations in cerebrospinal fluid as compared to intravenous CAR-T administration, a discovery that directly informs thier approach to enhancing patient durable responses. Utilizing a similar multi-omic approach in a GD2 CAR-T trial for pediatric solid tumors, they identified that T cell phenotype and myeloid state contribute to the immune environment permissive of CAR-T expansion and activity in patients. By bringing questions from the bedside back to the bench, Dr. Ramakrishna's laboratory’s research characterizes the immune biology that contributes to CAR-T efficacy in patients and develops the next generation of CAR-Ts to translate back to the bedside, with the ultimate goal of curing children with solid and brain tumors.