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

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Regular and Young Investigator Award Abstracts
Biomarkers, Immune Monitoring and Novel Technologies
166 High CTLA-4 transcriptomic expression correlates with high expression of other checkpoints and with outcome on immune checkpoint inhibitors
  1. Nithya Krishnamurthy1,
  2. Daisuke Nishizaki2,
  3. Scott M Lippman2,
  4. Hirotaka Miyashita3,
  5. Mary K Nesline4,
  6. Sarabjot Pabla4,
  7. Jeffrey M Conroy4,
  8. Paul DePietro4,
  9. Shumei Kato5 and
  10. Razelle Kurzrock6
  1. 1Icahn School of Medicine at Mount Sinai, New York, NY, USA
  2. 2Center for Personalized Cancer Therapy and Division of Hematology and Oncology, Department of Medicine, University of California San Diego, Moores Cancer Center, La Jolla, CA, USA
  3. 3Dartmouth Cancer Center, Lebanon, NH, USA
  4. 4Omniseq (Labcorp Oncology), Buffalo, NY, USA
  5. 5Moores UCSD Cancer Center, La Jolla, CA, USA
  6. 6Medical College of Wisconsin Froedtert Cancer Center, Milwaukee, WI, USA

Abstract

Background CTLA-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.

Methods We 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.

Results The 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).

Conclusions High 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.

http://creativecommons.org/licenses/by-nc/4.0/

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/jitc-2023-SITC2023.0166

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