Molecular, immune and microbial determinants of response and toxicity to combination CTLA-4 and PD-1 blockade

Treatment with combined immune checkpoint blockade (CICB) targeting cytotoxic T lymphocyte antigen-4 (CTLA-4) and programmed death receptor-1 (PD-1) is associated with clinical benefit across several tumor types but a high rate of immune related adverse events (irAE). Biomarkers of response and irAE to CICB represent an area of unmet medical need. To address this, we investigated genomic, immune and microbial determinants in a cohort of 53 metastatic melanoma (MM) patients and performed parallel studies in murine models. Results demonstrate similar biomarkers of response to checkpoint monotherapy, and also suggest that patients with a more antigen-experienced peripheral T cell repertoire (treated with prior immunotherapy) have a significantly lower rate of irAEs. Microbial determinants of response and toxicity to CICB were identified in the gut microbiota in human and murine cohorts, with commonalities, and evidence that targeting these taxa may reduce toxicity in preclinical models. Together, these findings have potentially important implications.

针对细胞毒性T淋巴细胞相关抗原4（cytotoxic T lymphocyte antigen-4, CTLA-4）与程序性死亡受体1（programmed death receptor-1, PD-1）的联合免疫检查点阻断（combined immune checkpoint blockade, CICB）治疗在多种肿瘤类型中均可带来临床获益，但伴随较高的免疫相关不良事件（immune related adverse events, irAE）发生率。针对CICB的应答与irAE生物标志物，是当前尚未满足的临床医疗需求领域。为此，我们对53例转移性黑色素瘤（metastatic melanoma, MM）患者队列开展了基因组、免疫与微生物组特征的研究，并在小鼠模型中进行了平行研究。研究结果显示，其应答生物标志物与检查点单药治疗相似，同时还提示，既往接受过免疫治疗、拥有更具抗原暴露经验的外周T细胞库的患者，其irAE发生率显著更低。在人类与小鼠队列的肠道菌群中，我们鉴定出了CICB应答与毒性的微生物组学决定因素，二者存在共性，且有证据表明，靶向这些菌群类群可在临床前模型中降低毒性反应。综上，这些发现具有潜在的重要意义。