Medline ® Abstracts for References 38-40
of 'Toxicities associated with checkpoint inhibitor immunotherapy'
Blockade of cytotoxic T-lymphocyte antigen-4 by ipilimumab results in dysregulation of gastrointestinal immunity in patients with advanced melanoma.
Berman D, Parker SM, Siegel J, Chasalow SD, Weber J, Galbraith S, Targan SR, Wang HL
Cancer Immun. 2010;10:11. Epub 2010 Nov 24.
Blockade of cytotoxic T-lymphocyte antigen-4 (CTLA-4) by ipilimumab leads to immune-mediated tumor regression and immune-related adverse events (irAEs), including diarrhea and colitis. The current analyses were undertaken to promote an understanding of the underlying mechanism of action and to identify potential biomarkers that could help in the prediction and management of ipilimumab-induced gastrointestinal irAEs. Treatment-naïve or previously treated patients with unresectable stage III/IV melanoma (n = 115) received open-label ipilimumab (10 mg/kg every 3 weeks for four doses) and were randomized to receive concomitant blinded prophylactic oral budesonide (9 mg/d with gradual taper through week 16) or placebo. Outcome measures included histologic assessment of bowel biopsies and assessment of serologic markers of inflammatory bowel disease (IBD), fecal calprotectin levels, and polymorphisms in immune-related genes. Ipilimumab resulted in dysregulation of gastrointestinal mucosal immunity as evidenced by altered antibody levels to enteric flora, inflammatory cell infiltration into gastrointestinal mucosa, and increased fecal calprotectin associated with diarrhea and clinical evidence of colitis. The pattern of ipilimumab-induced antibody titers to microbial flora and the histologic features and location of the inflammation were distinct from classic IBD. Prophylactic budesonide did not prevent ipilimumab-induced bowel inflammation. Despite an observed association between colonic inflammation and grade 2 or higher diarrhea, no baseline biomarkers could reliably predict development of gastrointestinal toxicity. Although classic IBD and ipilimumab-related gastrointestinal toxicity are both immune mediated, the observed pattern of biomarkers suggests ipilimumab-related gastrointestinal toxicity may be a distinct clinicopathologic entity.
Bristol-Myers Squibb Company, Princeton, New Jersey, USA. firstname.lastname@example.org
Tumor regression and autoimmunity in patients treated with cytotoxic T lymphocyte-associated antigen 4 blockade and interleukin 2: a phase I/II study.
Maker AV, Phan GQ, Attia P, Yang JC, Sherry RM, Topalian SL, Kammula US, Royal RE, Haworth LR, Levy C, Kleiner D, Mavroukakis SA, Yellin M, Rosenberg SA
Ann Surg Oncol. 2005 Dec;12(12):1005-16. Epub 2005 Oct 21.
BACKGROUND: Cytotoxic T lymphocyte-associated antigen (CTLA)-4 can inhibit T-cell responses and is involved in tolerance against self antigens. We previously reported autoimmune manifestations and objective cancer regressions in patients with metastatic melanoma treated with CTLA-4 blockade. The possibility of activating tumor-reactive T cells while removing inhibitory activity with CTLA-4 blockade has stimulated interest in using anti-CTLA-4 antibodies in combination with other cancer immunotherapies to improve clinical outcomes. In this study, we assessed the antitumor activity and autoimmune toxicity of CTLA-4 blockade in combination with an immune-activating stimulus, interleukin (IL)-2, in patients with metastatic melanoma.
METHODS: Thirty-six patients received anti-CTLA-4 antibody every 3 weeks. Three patients per cohort received doses of .1, .3, 1.0, and 2.0 mg/kg. Twenty-four patients received 3.0 mg/kg. All patients received IL-2 therapy (720,000 IU/kg every 8 hours to a maximum of 15 doses).
RESULTS: Eight patients (22%) experienced objective tumor responses (three complete and five partial), including metastases in the lungs, lymph nodes, mediastinum, and subcutaneous tissues. Six of the eight patients have ongoing objective responses at 11 to 19 months. Five patients (14%) developed grade III/IV autoimmune toxicities secondary to anti-CTLA-4 administration, including four patients with enterocolitis and one with arthritis and uveitis.
CONCLUSIONS: There is not evidence to support a synergistic effect of CTLA-4 blockade plus IL-2 administration, because the 22% objective response rate is that expected from the sum of these two agents administered alone. Durable cancer regressions were seen in patients treated with this combination.
Surgery Branch, National Cancer Institute, National Institutes of Health, CRC Room 3-3940, 10 Center Drive, MSC 1201, Bethesda, MD 20814, USA.
http://www.merck.com/product/usa/pi_circulars/k/keytruda/keytruda_pi.pdf (Accessed on September 08, 2014).
no abstract available