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Cancer Res. 2017 Mar 15;77(6):1322-1330. doi: 10.1158/0008-5472.CAN-16-2324. Epub 2016 Dec 28.

Immune Toxicities Elicted by CTLA-4 Blockade in Cancer Patients Are Associated with Early Diversification of the T-cell Repertoire.

Author information

1
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California.
2
Adaptive Biotechnologies, South San Francisco, California.
3
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California. lfong@medicine.ucsf.edu.

Abstract

While immune checkpoint blockade elicits efficacious responses in many patients with cancer, it also produces a diverse and unpredictable number of immune-related adverse events (IRAE). Mechanisms driving IRAEs are generally unknown. Because CTLA-4 blockade leads to proliferation of circulating T cells, we examined in this study whether ipilimumab treatment leads to clonal expansion of tissue-reactive T cells. Rather than narrowing the T-cell repertoire to a limited number of clones, ipilimumab induced greater diversification in the T-cell repertoire in IRAE patients compared with patients without IRAEs. Specifically, ipilimumab triggered increases in the numbers of clonotypes, including newly detected clones and a decline in overall T-cell clonality. Initial broadening in the repertoire occurred within 2 weeks of treatment, preceding IRAE onset. IRAE patients exhibited greater diversity of CD4+ and CD8+ T cells, but showed no differences in regulatory T-cell numbers relative to patients without IRAEs. Prostate-specific antigen responses to ipilimumab were also associated with increased T-cell diversity. Our results show how rapid diversification in the immune repertoire immediately after checkpoint blockade can be both detrimental and beneficial for patients with cancer. Cancer Res; 77(6); 1322-30. ©2016 AACR.

PMID:
28031229
PMCID:
PMC5398199
DOI:
10.1158/0008-5472.CAN-16-2324
[Indexed for MEDLINE]
Free PMC Article

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