Activating Low-Affinity T Cells to Prevent Relapse in Acute Lymphoblastic Leukemia

PROJECT SUMMARY/ABSTRACT Acute Lymphoblastic Leukemia (ALL) is the most common form of childhood cancer. Despite dramatic improvements in initial remission rates over the past 50 years, relapsed ALL remains a significant challenge and is the second leading cause of cancer-related death in children. Thus, ALL continues to pose a substantial health concern. The BCR-ABL fusion protein, resulting from a chromosomal translocation, is a key driver of leukemogenesis in ALL and serves as a promising target for immunotherapy due to its tumor-specific and essential role in oncogenesis. Studies have indicated that the presence of T cells specific for the BCR-ABL fusion epitope correlates with better leukemia control; however, vaccine-based strategies to elicit such protective T cell responses have not been successful. Our lab, together with our collaborator, has previously generated MHC class II tetramers linked to the BCR-ABL fusion peptide (BAp), which identified a small population of CD4+ T cells capable of recognizing this leukemia antigen. These BAp CD4+ T cells expanded in the presence of BCR-ABL+ leukemia but were often converted into immunosuppressive FOXP3⁺ regulatory T cells (Tregs) or dysfunctional type 1 regulatory (Tr1) like cells producing IL-10, limiting their effectiveness. Interestingly, combining tyrosine kinase inhibitors like nilotinib with anti-PD-L1 antibodies promoted Th1 CD4+ T cell responses and prevented relapse in murine models, suggesting that effective activation of BAp-specific T cells can enhance leukemia control. A key question that emerges is how to identify and activate T cells capable of sustaining durable anti-leukemia responses without succumbing to exhaustion or immunosuppressive conversion. We have collaborated with Dr. Dileepan to develop "affinity-enhanced" peptide-MHC class II tetramers (BAp) by augmenting the interaction between the MHCII β chain and the CD4 co-receptor, allowing us to identify and potentially activate these low-affinity T cells. I propose that activating low-affinity BAp-specific T cells using these affinity-enhanced reagents can generate potent and sustained anti-leukemia immunity. Thus, my central hypothesis is that a proper activation of low-affinity BAp CD4+ T cells is crucial for preventing relapse in ALL. This hypothesis will be tested in the following two specific aims: (1) Determine whether enhancing low-affinity BCR-ABL-specific T cell responses limits relapse, and (2) Determine the relationship between functional low-affinity BCR-ABL-specific T cells and clinical outcomes in ALL patients. Completion of these aims will further advance our understanding of how low-affinity T cells can be harnessed to generate durable anti-leukemia responses and how perturbation of these responses can lead to relapse in ALL. This research may lead to new immunotherapeutic strategies that improve survival outcomes for ALL patients and provide insights applicable to other cancers. Finally, this project will provide me with important training in the use of cutting-edge research tools and models, which are important skills for me to acquire as I embark on a career as a physician-scientist focused on cancer immunotherapy.