Abstract B142: Activation of endogenous anergic self-specific CD8+ T-cells by polymeric nanoparticles for enhanced cancer immunotherapy

Abstract

Abstract While the human immune system is often able to protect the body from infectious pathogens, it has multiple mechanisms to inhibit mounting an immune system against what it perceives as “self” and thus often fails to eliminate cancer cells since they seem to have the characteristics of “self.” Our lab found that cytotoxic CD8+ T-cells that recognize self antigens in the peripheral blood of healthy humans were present in frequencies similar to those specific for non-self antigens, but these self-specific CD8+ T-cells are resistant to activation and/or expansion. We hypothesized that tumor-infiltrating CD8+ T-cells recognizing self antigens are often in an anergized state but they could be activated with the appropriate immunostimulatory signals to augment antitumor immunity. Thus, we developed a poly(lactide-co-glycolide) nanoparticle (PLGA NP) based immunostimulatory platform that is surface-functionalized with monoclonal anti-CD28 antibody (Ab), and encapsulated interleukin-2 (IL-2), toll-like receptor-2 (TLR2) agonist and nucleotide-binding oligomerization domain-containing protein 2 (NOD2) in the hydrophobic core. This platform enables the encapsulated immunostimulatory drugs to be continuously released in the tumor microenvironment to activate the tumor infiltrating self-specific CD8+ T-cells in order to enhance antitumor immune response while minimizing the rapid diffusion of these drugs into other parts of the body, greatly reducing the systemic toxicities. Our results demonstrated that the mice bearing melanoma or colon cancers treated with the stimulatory PLGA NP have elicited potent T-cell response, resulting in marked tumor regression and increased overall survival. The developed PLGA NPs are also capable of generating an immunologic memory that prevented tumor growth after rechallenging the survivor mice with the same cancer cell type. Moreover, the developed PLGA NPs can be combined with checkpoint blocking antibodies to achieve the synergistic effect, significantly prolonging the overall survival. We also applied the single-cell TCR sequencing technique to assess both T-cell receptor and phenotypic characteristics of tumor-infiltrating CD8+ T-cells after NP stimulation. The result was further combined with yeast-display libraries of peptide-MHC to identify tumor-specific antigens. Citation Format: Qian Yin. Activation of endogenous anergic self-specific CD8+ T-cells by polymeric nanoparticles for enhanced cancer immunotherapy [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 B142.