“An HLA-Independent Booster Vaccine for CHimeric Antigen Receptor T cells”
Chimeric antigen receptor (CAR) T-cell therapy has shown dramatic clinical responses in hematologic malignancies, with a high proportion of durable complete remissions elicited in leukemia and lymphomas. However, achieving the full promise of CAR T-cell therapy, especially in solid tumors, will require further advances in this form of cellular therapy. A key challenge is maintaining a sufficient pool of functional CAR T cells in vivo. We recently developed a strategy to target vaccines to lymph nodes, by linking peptide antigens to albumin-binding phospholipid-polymers. Constitutive trafficking of albumin from blood to lymph makes it ideal chaperone to concentrate these “amphiphile-vaccine” molecules in lymph nodes that would otherwise be rapidly dispersed in the bloodstream following parenteral injection. These lipid-polymer conjugates also exhibit the property that they insert in cell membranes on arrival in lymph nodes. Here, we generated amphiphile CAR T ligand (amph-ligand) vaccine by exploiting these dual lymph node targeting and membrane-decorating properties to repeatedly expand and rejuvenate CAR T cells through the chimeric receptor in native lymph node microenvironment. We evaluated this approach in the presence of a complete host immune system. Amph-ligand vaccine boosting triggered massive CAR T expansion, increased donor cell polyfunctionality, and enhanced anti-tumor efficacy in multiple immunocompetent tumor models. We demonstrate two approaches to generalize this strategy to any CAR, enabling this simple HLA-independent vaccination approach to enhance CAR T functionality to be applied to existing CAR T cell designs. Taken together, our amph-ligand vaccine provides a simple engineering solution to augment CAR T-cell therapy.