Abstract 6476: Microbiome modulation via CBM588 dampens T cell exhaustion in patients with metastatic renal cell carcinoma on dual immune checkpoint blockade

Abstract Background: Immune checkpoint inhibitors (ICIs) are well-described to augment T cell responses and boost anti-tumor immune responses, with increased survival benefits of patients with a number of different indications treated with a variety of PD-1, PD-L1, or CTLA-4 targeting monoclonal antibodies. While the combination of nivolumab (nivo) and ipilimumab (ipi) is currently one of the standard-of-care treatments for patients with metastatic renal cell carcinoma (mRCC), the majority of patients still suffer disease progression. CBM588 is a live biotherapeutic product that has previously demonstrated ability to enhance clinical responses to nivo+ipi treatment in patients with mRCC. In our current study, we sought to explore immune correlatives of patients treated with nivo+ipi alone as compared to those treated with CBM588+nivo+ipi. Methods: Peripheral blood was collected from patients with mRCC treated across two clinical trials: the initial CBM588+nivo+ipi study (NCT0382911) and an ongoing CBM588 dose finding study of patients with (NCT06399419). Both trials enrolled treatment-naïve patient with mRCC with clear cell and/or sarcomatoid histology. The initial trial enrolled patients with or without CBM588 co-treatment at a 2:1 ratio. The initial trial enrolled patients treated with or without CBM588 at 4 × 108 CFU/dose, while the dose escalation study followed a 3+3 design with three dose levels of CBM588 (4 × 108 CFU, 1.2 × 109 CFU, and 4 × 109 CFU). Cryopreserved blood was thawed and analyzed by high parameter spectral flow cytometry for overall immune composition and detailed T cell phenotyping. Results: No significant differences were observed in myeloid cell or innate lymphocyte changes between patients treated with or without CBM588. Increased frequencies of proliferating CD8+ T cells (Ki-67+) were observed across all patients from baseline to Cycle 3 Day 1. The expansion of proliferating CD8+ T cells was significantly less accelerated in patients treated with CBM588+nivo+ipi as compared to those treated with nivo+ipi alone. Notably, the expanding Ki-67+ CD8+ T cell population identified demonstrated features of T cell exhaustion with less expression of CD127 (IL-7R) and higher expression of CD38, KLRG1, TIM-3 relative to other circulating CD8+ T cell populations. Conclusions: Our results suggest that CBM588 may improve patient responses to ICIs by restraining CD8+ T cell amplification and attenuating features of T cell exhaustion. The CBM588+nivo+ipi dose escalation study is still ongoing with further immune correlative analyses pending. Citation Format: Colt A. Egelston, Miguel Zugman, Hedyeh Ebrahimi, Regina Barragan Carrillo, Nazli Dizman, Salvador Jaime-Casas, Xiaochen Li, Daniela V. Castro, Benjamin Mercier, Marice Alcantara, Motomichi Takahashi, Atsushi Hayashi, Tom Parks, Sumanta Kumar Pal, Peter P. Lee, Alexander Chehrazi-Raffle. Microbiome modulation via CBM588 dampens T cell exhaustion in patients with metastatic renal cell carcinoma on dual immune checkpoint blockade [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6476.