Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma

Ralph, C; Elkord, E; O'Dwyer, J; Austin, E

Abstract

Purpose: Cytotoxic T lymphocyte antigen 4 (CTLA4), a key negative regulator of T-cell activation, is targeted by the antibody tremelimumab to release potentially useful antitumor activity.
Experimental design: This phase II trial investigated tremelimumab as a second-line treatment for patients with metastatic gastric and esophageal adenocarcinomas. Tremelimumab was given every 3 months until symptomatic disease progression. Safety, clinical efficacy, and immunologic activity were evaluated.

RESULTS: Eighteen patients received tremelimumab. Most drug-related toxicity was mild; however, there was a single death due to bowel perforation that complicated colitis. Four patients had stable disease with clinical benefit; one patient achieved a partial response after eight cycles (25.4 months) and remains well on study at 32.7 months. Markers of regulatory phenotype, forkhead box protein 3 and CTLA4, doubled transiently in CD4(+)CD25(high) lymphocytes in the first month after tremelimumab before returning to baseline. In contrast, CTLA4 increased in CD4(+)CD25(low/negative) lymphocytes throughout the cycle of treatment. De novo proliferative responses to tumor-associated antigens 5T4 (8 of 18 patients) and carcinoembryonic antigen (5 of 13) were detected. Patients with a posttreatment carcinoembryonic antigen proliferative response had median survival of 17.1 months compared with 4.7 months for nonresponders (P = 0.004). Baseline interleukin-2 release after T-cell activation was higher in patients with clinical benefit and toxicity.

CONCLUSION: Despite the disappointing response rate of tremelimumab, one patient had a remarkably durable benefit for this poor-prognosis disease. In vitro evidence of enhanced proliferative responses to relevant tumor-associated antigens suggests that combining CTLA4 blockade with antigen-targeted therapy may warrant further investigation.

Citation

Ralph, C., Elkord, E., O'Dwyer, J., & Austin, E. (2010). Modulation of lymphocyte regulation for cancer therapy: a phase II trial of tremelimumab in advanced gastric and esophageal adenocarcinoma. Clinical Cancer Research, 16(5), 1662-1672. https://doi.org/10.1158/1078-0432.CCR-09-2870

• Journal Article Type: Article
• Publication Date: Feb 1, 2010
• Deposit Date: Oct 12, 2011
• Journal: Clinical Cancer Research
• Print ISSN: 1078-0432
• Publisher: American Association for Cancer Research
• Peer Reviewed: Peer Reviewed
• Volume: 16
• Issue: 5
• Pages: 1662-1672
• DOI: https://doi.org/10.1158/1078-0432.CCR-09-2870
• Publisher URL: http://dx.doi.org/ 10.1158/1078-0432.CCR-09-2870