通过CBM588调节微生物组可减弱接受双重免疫检查点阻断的转移性肾细胞癌患者的T细胞耗竭

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 × 10 8 CFU/dose, while the dose escalation study followed a 3+3 design with three dose levels of CBM588 (4 × 10 8 CFU, 1.2 × 10 9 CFU, and 4 × 10 9 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.