Abstract 4439: Negative impact of the GABA pathway on aPD(L)1 immunotherapy

Abstract Although gamma-amino butyric acid (GABA) is well characterized as the primary inhibitory neurotransmitter of the central nervous system, its role in the periphery as an immunomodulatory agent is not well understood. Given the widespread use of GABA-A receptor agonists as palliative care in clinical practice, we examined here the impact of GABA on response to immunotherapy in preclinical tumor models and the association of GABA-A receptor agonist usage with outcomes in patients receiving immunotherapy.We show that important genes controlling the GABA pathway are enriched in human tumors versus normal tissue across indications, and tumor cells themselves are able to produce GABA. We found that several key genes of the GABA pathway are upregulated in non-responders to atezolizumab and we derived a 5-gene signature associated with poor outcomes in 2L urothelial cancer patients receiving atezolizumab. Preclinical models further indicated that GABA at the tumor site promotes tumor growth and dampens adaptive immunity preventing response to immunotherapy. Finally, we noted that 45% of urothelial cancer patients received concomitant GABA-A positive allosteric modulators, given as palliative therapy in atezolizumab trials IMvigor-210 and -211. This group exhibited significantly lower OS and PFS as compared to atezolizumab treated patients who did not receive GABA-A positive modulators. A similar negative impact was seen in patients receiving standard of care anti-PD(L)1 immunotherapy in 2L NSCLC using EHR derived deidentified Flatiron Health - Komodo Health claims linked data. These findings highlight the need for further evaluation of concomitant GABA modulators to understand potential risk associated with palliative care in the setting of cancer immunotherapy. © [2022] Komodo Health, Inc All rights reserved Reproduction, distribution, transmission or publication is prohibited Reprinted with permission. Citation Format: Svetlana Lyalina, Guadalupe Ortiz-Munoz, Kobe Yuen, Ira Mellman, Sanjeev Mariathasan, Matthew Albert, Deepti Nagarkar, Christine Moussion. Negative impact of the GABA pathway on aPD(L)1 immunotherapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4439.