Abstract B27: Blockade of protein kinase A (PKA) localization augments the trafficking and anti-tumor efficacy of adoptively transferred chimeric antigen receptor-expressing T cells

Abstract

Abstract Infusion of T cells expressing chimeric antigen receptors (CAR T cells) is still relatively ineffective in solid tumors due to the presence of immunosuppressive mediators (such as prostaglandin E2 (PGE2) and adenosine), and poor T cell trafficking. Since PGE2 and adenosine activate protein kinase A (PKA), which then inhibits T cell receptor (TCR) activation, we generated CAR T cells that expressed a small peptide called the “regulatory subunit I anchoring disruptor” (RIAD) that inhibits the association of protein kinase A (PKA) with ezrin; this interaction is required for the negative effects of PKA on TCR activation. After exposure to PGE2 or adenosine in vitro, CAR-RIAD T cells showed increased TCR signaling, more cytokine release, and enhanced killing of tumor cells compared to CAR T cells. When injected into tumor-bearing mice, murine and human CAR-RIAD T cells demonstrated enhanced anti-tumor efficacy compared to CAR T cells due to increased T cell infiltration of established tumors, and attenuated tumor-induced hypofunction. Subsequent in vitro assays showed that both mouse and human CAR-RIAD cells migrated more efficiently than CAR cells in response to the chemokine CXCL10 and also adhered better to various matrices. Our data therefore show that the addition of the RIAD peptide to adoptively transferred CAR T cells augments their efficacy by increasing their effector function and by improving trafficking into tumor sites. This treatment strategy should therefore be considered for clinical application in treating solid tumors. Citation Format: Kheng Newick, Shaun O'Brien, Jing Sun, Veena Kapoor, Steve Maceyko, Albert Lo, Ellen Pure, Ed K. Moon, Steven M. Albelda. Blockade of protein kinase A (PKA) localization augments the trafficking and anti-tumor efficacy of adoptively transferred chimeric antigen receptor-expressing T cells. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr B27.