166 High CTLA-4 transcriptomic expression correlates with high expression of other checkpoints and with outcome on immune checkpoint inhibitors

• Published in: Journal for immunotherapy of cancer Vol. 11; no. Suppl 1; p. A187
• Main Authors: Krishnamurthy, Nithya, Nishizaki, Daisuke, Lippman, Scott M, Miyashita, Hirotaka, Nesline, Mary K, Pabla, Sarabjot, Conroy, Jeffrey M, DePietro, Paul, Kato, Shumei, Kurzrock, Razelle
• Format: Journal Article
• Language: English
• Published: London BMJ Publishing Group Ltd 01-11-2023; BMJ Publishing Group LTD; BMJ Publishing Group
• Subjects: Cancer; Cervical cancer; Immunotherapy; Regular and Young Investigator Award Abstracts; Tumors
• ISSN: 2051-1426
• DOI: 10.1136/jitc-2023-SITC2023.0166

BackgroundCTLA-4 is a membrane glycoprotein expressed by activated effector T cells that impedes the immune system’s antitumor response. There are two FDA-approved anti-CTLA-4 agents—ipilimumab and tremelimumab, both used together with anti-PD-1/PDL1 agents.MethodsWe evaluated RNA expression levels (OmniSeq (https://www.omniseq.com)) and clinical correlates of CTLA-4 and other immune checkpoints in 514 tumors. A reference population (735 tumors; 35 histologies) was used to normalize transcript abundance to internal housekeeping gene profiles and rank transcript abundance (0–100 percentile). Altogether, 217 patients (42.2% of 514) received immune checkpoint inhibitor (ICI) therapy. Kaplan Meier was utilized for progression-free-survival (PFS) and overall survival (OS) analyses.ResultsThe most common tumor types were colorectal (140/514, 27%), pancreatic (55/514, 11%), breast (49/514,10%), and ovarian cancer (43/514, 8%). Overall, 87 of 514 tumors (16.9%) had high CTLA-4 transcript expression (≥75 percentile). Cancers with the greatest proportion of high CTLA-4 transcripts were cervical cancer (80% of patients), small intestine cancer (33.3%), and melanoma (33.3%). Across cancers, high CTLA-4 RNA was seen in 16.9% of tumors (87/514) and correlated with high PD-1, PD-L2, and LAG3 (but not with high PD-L1) expression (all p<0.05 multivariate analysis). High CTLA-4 RNA expression did not correlate with survival from time of metastatic disease (N=272 patients who did not receive ICI). In 217 patients treated with ICIs (anti-PD1/PDL1 agents alone in 199 patients; regimen included anti-CTLA4 agent in 18 patients), PFS and OS correlated with high levels of CTLA-4. In the high (>75 RNA percentile rank) versus moderate/low (<75 percentile rank) CTLA4 groups, median PFS was 7.7 months (N=41) versus 4.6 months (N=176) (hazard ratio (HR) 0.6 (95% confidence interval (CI) 0.4–0.9), p=0.008); median OS was 39.6 versus 14.5 months (HR, 95% CI 0.5 (0.3–0.8), p = 0.002).ConclusionsHigh CTLA-4 expression was not a prognostic factor for survival in patients not receiving ICIs but was a significant positive predictive biomarker for better outcome (PFS and OS) in patients on immunotherapy, perhaps because of its correlation with expression of other checkpoints such as PD-1 and PD-L2.