Abstract 642: Peripheral immune cells associated with toxicity to ipilimumab plus nivolumab checkpoint blockade in patients with metastatic melanoma

Background: Immune checkpoint blockade (ICB) has revolutionized clinical outcomes in melanoma. Compared with single ICB (aCTLA-4, aPD-1), combination ICB aCTLA-4 plus aPD-1 shows the highest response rate, with 50%-60% patients responding to treatment. However, it also has the highest toxicity rate, with about 50% patients developing high grade toxicity. Identifying circulating immune cells as biomarkers to predict toxicity could guide clinical decisions and shed light on potential mechanisms driving toxicity. Methods: We identified and quantified circulating immune cells proportions using CyTOF (cytometry by Time-Of-Flight), measured cytokines using Luminex, and collected complete blood counts from 89 patients with metastatic melanoma treated with combination therapy. Samples were obtained from three points in time: pre-treatment, one month and approximately three months after treatment started. We then evaluated the association between circulating immune cells, cytokines, clinical labs values, and high grade toxicities (grade >=3 or grade 2 requiring treatment). We also investigated the co-occurrence patterns of toxicity at various organs systems, as well as the onset timing of different grades of toxicities. Results: Most high grade toxicities occurred between 3 and 18 weeks after start of therapy, consistent with prior studies. Interestingly, we found a statistically significant mutual exclusivity of high grade lung and gastrointestinal toxicities (Fisher’s exact, p = 0.01, OR = 0). In contrast to prior results, we found that in pre-treatment blood samples higher naïve T cells, lower central memory T cells (TCM) and effector memory T cells (TEM) are associated with development of high grades toxicities (MWW, p = 0.002, p = 0.043, p = 0.009). A greater increase in CD8+ TEMs from pre to post1 time points (MWW, p = 0.047), while a lower increase in basophils (MWW, p = 0.030), was associated with patients with high grade toxicities. Conclusions: Collectively, our findings help gain more insights into the development of toxicities, and could ultimately guide the development of personalized strategies for toxicities prevention, surveillance, and mitigation in melanoma patients treated with combination immunotherapy. Citation Format: Jiajia Chen, Joanna Baginska, Giuseppe Tarantino, Kelly Burke, Elad Sharon, Anita Giobbie-Hurder, Jason L. Weirather, Michael Manos, Janice D. Russell, Ryan Brennick, Matthew Nazzaro, Emma Hathaway, Marta Holovatska, Claire Manuszak, Srinika Ranashinge, David Liu, F. Stephen Hodi. Peripheral immune cells associated with toxicity to ipilimumab plus nivolumab checkpoint blockade in patients with metastatic melanoma [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 642.