Deciphering interactions between human T cells and cardiomyocytes in immune checkpoint inhibitor-related myocarditis

Severe immune-related adverse events (irAEs) such as immune checkpoint inhibitor-related myocarditis (irMyocarditis) are poorly understood and potentially life-threatening side effects caused by immune checkpoint inhibitors (ICIs). Steven Blum, MD is an Instructor of Medicine at Harvard Medical School and an Assistant in Medicine at the Massachusetts General Hospital (MGH) in the Division of Hematology/Oncology. His long-term goal as a physician scientist is to utilize patient samples and human models to design therapeutic strategies that reduce the impact of irAEs – starting with irMyocarditis – without blunting ICI efficacy. The overall objective for this application is to determine the drivers of irMyocarditis and therapeutically modulate interactions between T cells and cardiomyocytes using patient samples and model systems. The central hypothesis is that autoreactive T-cell clones expanded in irMyocarditis tissue recognize novel autoantigens and utilize targetable programs to drive irMyocarditis pathogenesis that are distinct from programs driving anti-tumor immunity. The rationale for this project is that the T cell-mediated killing of cardiomyocytes defines the pathology of irMyocarditis, but the interactions between these cell types remain poorly defined. Dr. Blum will test this hypothesis through three specific aims: (1) define cardiomyocyte-reactive T-cell clones; (2) identify pathogenic interactions between T cells and non-immune cells; and (3) modulate T cells therapeutically to prevent cardiomyocyte death while allowing tumor cell killing in vitro. In Aim 1, he will determine which T-cell receptors (TCRs) isolated from the hearts of irMyocarditis patients recognize cardiomyocytes and identify antigens recognized by these TCRs. In Aim 2, he will use spatial profiling approaches to identify targetable interactions between T cells and non-immune cells. In Aim 3, he will test potential therapies in parallel co-culture models of (i) T cells with cardiomyocytes and (ii) T cells with tumor cells. He will then develop a clinical trial protocol to test the efficacy of a candidate treatment to mitigate irMyocarditis in patients. This research can offer significant contributions to the understanding and management of irMyocarditis and irAEs more broadly. Dr. Blum has outlined a five-year career development plan consisting of coursework, conferences, seminars, and structured mentoring in T-cell manipulation, antigen recognition techniques, spatial transcriptional profiling, and in vitro co- culture modeling to perform his research and reach his goal of becoming an independent investigator. Dr. Blum will pursue the training outlined in this K08 Award proposal under the guidance of an experienced, interdisciplinary mentoring and advisory team from MGH, the Dana-Farber Cancer Institute (DFCI), and the Broad Institute. His team is led by his primary mentor, Dr. Alexandra-Chloé Villani (MGH), and includes his co- mentors, Drs. Ryan Sullivan (MGH) and Catherine Wu (DFCI). He will maintain ≥80% of his time for research. Training in this exceptional environment will help Dr. Blum obtain the necessary experience and skills to become an R01-funded independent investigator in the field of immuno-oncology. Project Number: 1K08AI197864-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute of Allergy and Infectious Diseases (NIAID) | Principal Investigator: Steven Blum | Institution: MASSACHUSETTS GENERAL HOSPITAL, BOSTON, MA | Award Amount: $197,640 | Activity Code: K08 | Study Section: Career Development Study Section (J)[NCI-J] View on NIH RePORTER: https://reporter.nih.gov/project-details/1K08AI19786401A1