Abstract 3846: The obesity paradox in immune checkpoint blockade: A pan-tumor analysis

Abstract Background: Chronic systemic inflammation mediated by pro-inflammatory cytokines serves as a major mechanism by which obesity contributes to cancer development. Paradoxically, elevated body mass (BMI) has been associated with improved outcomes after treatment with immune checkpoint inhibitors (ICIs) in many tumor types. The interplay between cytokine response and obesity after ICIs is poorly understood. To characterize underlying mechanisms, we investigated cytokine profiles in relation to obesity and clinical outcomes in patients treated with ICIs. Methods: From June 2021 to October 2022, we enrolled and collected blood samples from patients with advanced or metastatic solid tumors who received ICIs as standard of care at Johns Hopkins. We calculated BMI using height and weight at treatment initiation, with BMI ≥30 obese and BMI <30 non-obese. Underweight patients (BMI <18.5) were excluded. The Bioplex 200 platform (Biorad, Hercules CA) was used to determine the plasma concentration of 37 cytokines at baseline and on-treatment, with the median cytokine value used to differentiate between high and low concentration. Results: Among 94 patients, 29 (31%) were obese and 65 (69%) were non-obese, with a significant difference in sex (Fisher’s exact test, p = 0.02), but no observed difference in age, race, cancer type, autoimmune disease, or presence of immune-related adverse events (irAE) based on BMI category; all the following hazard ratios (HR) are therefore adjusted for sex. Obese patients had improved progression free survival (PFS) (HR 0.41 [95% CI: 0.21-0.80], p=0.01) and overall survival (OS) (HR 0.16 [95% CI: 0.04-0.69], p=0.01). Eighty-six patients had cytokine data at baseline (range: eight days prior to day of initiation). Baseline IL-15 was significantly lower in obese patients (1.71 vs. 2.08, p=0.04), however, there was no difference in PFS (HR 1.49 [95% CI: 0.87-2.56], p=0.15) or OS (HR 1.22 [95% CI: 0.51-2.97], p=0.65) comparing low vs. high baseline IL-15. Eighty-two patients had cytokine data on-treatment (range: 21-349 days after initiation), with significantly lower levels of IL-6 (2.49 vs. 3.45, p=0.04), IL-8 (2.01 vs. 2.92, p=0.01), and IL-15 (1.70 vs. 1.81, p=0.01) in obese vs. non-obese patients, respectively. Low on-treatment IL-8 was associated with improved PFS (HR 0.52 [95% CI: 0.29-0.92], p=0.02) and OS (HR 0.17 [95% CI: 0.05-0.58], p<0.01), and low on-treatment IL-6 was associated with improved OS (0.25 [95% CI: 0.08-0.76], p=0.01). Conclusions: In a diverse, pan-tumor ICI cohort, we observed a positive relationship between obesity and clinical outcomes with ICIs, with no correlation between obesity and irAEs. We also observed lower on-treatment levels of IL-6 and IL-8 in patients with obesity and that low on-treatment levels of IL-6 and IL-8 correlated with improved survival, suggesting that IL-6 and IL-8 may serve as mediating factors for improved outcomes in obese patients treated with ICIs. Citation Format: Stephanie Leigh Alden, Soren Charmsaz, Madelena Brancati, Howard L. Li, Aanika Warner, Kabeer Munjal, Kathryn Howe, Sarah Mitchell, Ervin Griffin, Mari Nakazawa, Hua-Ling Tsai, Ludmila Danilova, Chris Thoburn, Jennifer Gizzi, Alexei Hernandez, Nicole E. Gross, Erin M. Coyne, Sarah M. Shin, Jennifer Durham, Maximilian F. Konig, Brian J. Christmas, Evan J. Lipson, Jarushka Naidoo, Laura C. Cappelli, Aliyah Pabani, Yasser Ged, Marina Baretti, Julie R. Brahmer, Jean Hoffman-Censits, Tanguy Y. Seiwert, Sanjay Bansal, Laura Tang, Elizabeth Jaffee, G Scott Chandler, Rajat Mohindra, Won Jin Ho, Mark Yarchoan, Chester Kao. The obesity paradox in immune checkpoint blockade: A pan-tumor analysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3846.