Abstract 5592: Sec61 inhibitor KZR-834, an anti-cancer agent, exhibits immunomodulatory activity and combines with PD-1 blockade to further enhance immune responses

Abstract

Abstract KZR-261 is a first-in-class small molecule Sec61 inhibitor currently in a Phase I clinical trial in patients with advanced solid tumors (NCT05047536). We previously reported that KZR-261 and KZR-834, a structural analog, potently blocked the expression of various cancer and immune checkpoint-associated secreted and cell surface Sec61 client proteins. This inhibition profile corresponded to broad anti-cancer activity in vitro and in vivo across multiple solid and hematologic tumor types. Previously presented data demonstrated additive anti-tumor response with KZR-834 in combination with anti-PD-1 antibody in the MC38 syngeneic mouse colon tumor model. Based on these data, we were interested in further characterizing the immunomodulatory potential of Sec61 inhibitors. Following treatment with KZR-834 alone or in combination with anti-PD-1 antibody, we examined immune cell subsets in excised MC38 tumors by flow cytometry or RNA-seq. Once weekly administration of KZR-834 delayed tumor growth by 40%, while biweekly treatment with anti-PD-1 antibody delayed tumor growth by 66%. Strikingly, the combination with KZR-834 and anti-PD-1 antibody delayed tumor growth by 127%, and 3 of 10 mice had complete tumor regression on Day 45 (end of study). KZR-834 treatment reduced PD-L1 expression on tumor cells and resulted in 50-80% reduction in the frequency of PD-L1+ tumor-infiltrating myeloid cells (dendritic cells, macrophages, monocytic and granulocytic myeloid cells). In addition, the frequency of MHCII+ CD86+ PD-L1- dendritic cells and macrophages were increased with KZR-834 treatment. These changes were not detected with anti-PD-1 antibody treatment alone. PD-1+ CD8 T cells were elevated with single agent KZR-834 but not observed in other treatment groups. The combination treatment with KZR-834 and anti-PD-1 increased the numbers of activated CD69+, CD25+, and CD44+ CD8 T cells/mm3 of tumor when compared to vehicle treatment. A similar trend was detected in activated CD4 T cells. RNA-seq analysis of tumor tissues identified elevated IFNγ and T-bet gene expression with combination treatment further indicating T cell changes. In addition, anti-tumor gene signatures for T cells, NK and M1 cells were induced by KZR-834 and anti-PD-1 combination treatment. Taken together, these results suggest that KZR-834, in addition to its potent anti-cancer activity, has the potential to modify PD-L1 expression on antigen presenting cells thereby increasing antigen-experienced T cells within the tumor. Specifically, in the MC38 tumor model, KZR-834 combines with anti-PD-1 antibody to enhance immune responses. These data support further investigation into combining KZR-834 with immune checkpoint inhibitors to potentiate anti-tumor activity. Citation Format: Jennifer A. Whang, Andrea Fan, Jing Jiang, Christopher J. Kirk, Tony Muchamuel. Sec61 inhibitor KZR-834, an anti-cancer agent, exhibits immunomodulatory activity and combines with PD-1 blockade to further enhance immune responses [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 5592.