Abstract 5586: Demonstrating restoration of T cell function in exhausted T cells with IKZF3 small molecule inhibitor, Lenalidomide

Abstract

CD8+ T cell exhaustion as a result of prolonged antigenic stimulation in the tumour microenvironment is thought to be a major mechanism by which tumours can escape immune surveillance. T cell exhaustion is characterised by co-expression of checkpoint inhibitor molecules such as PD-1, LAG-3 and TIM-3; reduced proliferative capacity; and diminished production of pro-inflammatory cytokines such as IL-2, IFN-γ and TNF-α and treatment with checkpoint inhibitor blockade such as Nivolumab (anti-PD-1) have shown great promise in the treatment of a subset of individuals and tumour types. However, resistance to these approaches is prevalent and there is a need to identify novel targets to provide alternative options for the rescue of T cell exhaustion and cancer treatment for use alone or potentially in combination with checkpoint inhibitor modulation. One such target is IKZF3, a transcription factor that is increased in murine models of T cell exhaustion and reduces IL-2 expression. Previously we presented an in vitro human T cell exhaustion assay whereby in vitro stimulated T cells phenotypically and functionally recapitulate the exhausted T cells found within the tumour microenvironment and now we demonstrate that exhaustion can be partially rescued by treatment with the IKZF3 small molecule inhibitor, Lenalidomide, alone and in combination with checkpoint inhibitor blockade. The use of small molecule inhibitors offers new avenues for reversing T cell exhaustion in cases of checkpoint inhibitor resistance and this platform delivers a robust assay allowing for assessment of small molecules or checkpoint inhibitors both individually and in combination. Citation Format: Joanne Hay, Francis Acklam, Darryl Turner, Mark Barbour, Preeti Singh, Courtney Grant, Hayley Gooding, Rhoanne McPherson, Justyna Rzepecka. Demonstrating restoration of T cell function in exhausted T cells with IKZF3 small molecule inhibitor, Lenalidomide [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5586.

Degradation of IKAROS prevents epigenetic progression of T cell exhaustion in a novel antigen-specific assay

“…In our ATAC-seq dataset from iberdomide treated T cells, our list of differential peaks had the highest overlap with IKAROS ChIP-seq datasets, suggesting that IKAROS degradation contributes significantly to the observed phenotype. Interestingly, the IMID lenalidomide has been reported to partially rescue T cell exhaustion through AIOLOS degradation 58 . AIOLOS degradation also enhanced CAR-T cell proliferation and activity 59 , suggesting that IKAROS and AIOLOS may have similar roles in T cell exhaustion.…”