Abstract IA37: Enhancing the function of CAR T cells via a universal vaccine strategy

Abstract

Abstract We recently developed a strategy to target peptide vaccines to lymph nodes, by linking peptide antigens to albumin-binding phospholipid-polymers. Small peptides are normally rapidly dispersed in the bloodstream following parenteral injection, but binding of amphiphile-peptides to endogenous albumin, which constitutively traffics from blood to lymph, retargeted these molecules to lymph nodes. However, these lipid-polymer conjugates bind to albumin with a relatively low affinity, and these molecules can also partition into cell membranes. We hypothesized that by attaching a small molecule, peptide, or protein ligand for a chimeric antigen receptor (CAR) to the same polymer-lipid tail (forming an “amph-vax” molecule), CAR ligands could be delivered efficiently to lymph nodes by albumin and subsequently partition into membranes of resident antigen presenting cells (APCs), thereby co-displaying a CAR T cell ligand from the cell surface together with native cytokine/receptor costimulation. In syngeneic mouse models of adoptive cell therapy, we demonstrated that this approach effectively concentrates CAR T ligands on the surfaces of dendritic cells in lymph nodes, leading to profound expansion of amph-vax-boosted CAR T cells in vivo. Amph-vax boosting safely increased the polyfunctionality of CAR T cells in parallel with T cell expansion. In a syngeneic model of melanoma, this converted a CAR T treatment that had no impact on tumor progression to a therapy that strongly delayed tumor outgrowth and enhanced survival. We have reduced to practice three different strategies to generalize this approach to any CAR of interest. This concept provides a strategy to regulate the expansion and function of CAR T cells directly in vivo to enhance adoptive cell therapy of cancer. Citation Format: Darrell J. Irvine. Enhancing the function of CAR T cells via a universal vaccine strategy [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA37.