Abstract 2249: Selective degradation of Helios induces Treg cell reprogramming and enhanced antitumor immunity

Abstract Regulatory T (Treg) cell suppression of antitumor immunity can limit responses to immunotherapy in multiple solid tumor indications. The transcription factors Helios (IKZF2) and Eos (IKZF4) are abundantly expressed by Treg cells in the tumor microenvironment and act as critical nodes in a transcriptional network that enforces a stable immunosuppressive Treg cell phenotype. In preclinical models, inducible genetic loss of Helios in Foxp3-expressing Treg cells alone or with anti-PD-1 immune checkpoint blockade yields improved or complete responses to subcutaneous MC38 tumors, respectively, highlighting Helios as a druggable target for immunotherapy. BMS-986449 is a CELMoD molecular glue that redirects the E3 ubiquitin ligase Cereblon to interact with and induce the degradation of Helios and Eos. It was optimized to induce rapid and deep degradation of Helios and Eos in primary Treg cells with selectivity over other CELMoD neosubstrates, as assessed by global proteomic analysis of primary T cells. When primary human Treg cells were cultured under activating conditions with BMS-986449, a reprogrammed transcriptional phenotype emerged by 8 days in culture, including increased protein expression of effector molecules, such as Granzyme B, and abundant expression of inflammatory gene transcripts. In tumor bearing hCRBN-KI mice, BMS-986449 daily dosing induced monotherapy activity in the CT26, MB49, and MC38 tumor models with TGI values of up to 75%, 62%, and 42%, respectively; in combination with anti-PD-1 immune checkpoint blockade more robust efficacy was achieved with TGI values of 95%, 97%, and 92%, respectively. Additionally, in cynomolgus monkeys, daily dosing of BMS-986449 (0.1 mg/kg) maintained greater than 80% degradation of Helios in circulating Treg cells, supporting the advancement of BMS-986449 into Phase 1/2 clinical trials for patients with advanced solid tumors. Citation Format: Michael J. Barnes. Selective degradation of Helios induces Treg cell reprogramming and enhanced antitumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 2249.