Abstract B12: Inhibition of the transcription factor Ikaros augments the tumoricidal capacity of CD8+ T cells expressing chimeric antigen receptor

Recent success of adoptive transfer of T cells expressing chimeric antigen receptors (CARs) in patients with blood-borne malignancies has resulted in growing enthusiasm to apply the same approach to treat solid tumors. CAR-expressing T cells, however, will likely face many challenges that will limit their efficacy in solid tumors. One possible obstacle will be the intrinsic negative feedback system that prevent continuing T cell responses. The transcription factor Ikaros, which has been shown to suppress endogenous T effector functions through epigenetic remodeling of cytokine gene loci, may be one such negative regulator. Here we show that anti-mesothelin CAR (mesoCAR) T cells with reduced levels of Ikaros consistently mediate better in vitro cell killing and in vivo tumor regression than their wild-type counterparts. This increased anti-tumor activity was accompanied by increased persistence of mesoCAR T cells, as well as increased IFN-γ production. Enhanced cytolytic activity was also evidenced in mesoCAR T cells with reduced Ikaros, which could be partially explained by increased CD107a upregulation and Granzyme B production. Reduction in the Ikaros level in mesoCAR T cells did not affect T cell receptor and CAR signaling, but was able to render them more resistant to soluble inhibitory factors like TGF-β and adenosine. In summary, inhibition of the transcriptional repressor Ikaros in CAR T cells could be an attractive strategy to overcome immunosuppressive tumor microenvironment and enhance their tumoricidal capacity. Further clinical development is warranted.

Citation Format: Shaun O'Brien, Rajan M. Thomas, Steven M. Albelda, Andrew D. Wells, Liang-Chuan S. Wang. Inhibition of the transcription factor Ikaros augments the tumoricidal capacity of CD8+ T cells expressing chimeric antigen receptor. [abstract]. In: Proceedings of the AACR Special Conference: Tumor Immunology and Immunotherapy: A New Chapter; December 1-4, 2014; Orlando, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2015;3(10 Suppl):Abstract nr B12.