期刊
CLINICAL CANCER RESEARCH
卷 20, 期 9, 页码 2424-2432出版社
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-13-2648
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资金
- Melanoma Research Foundation, NIH [2U54 CA151819, R01 CA170689, P01 CA168585]
- Seaver Institute
- Dr. Robert Vigen Memorial Fund
- Wesley Coyle Memorial Fund
- Garcia-Corsini Family Fund
- Louise Belley and Richard Schnarr Fund
- Bila Alon Hacker Memorial Fund
- Fred L. Hartley Family Foundation
- Ruby Family Foundation
- Jonsson Cancer Center Foundation
- Caltech-UCLA Joint Center for Translational Medicine
- Stand Up To Cancer-Cancer Research Institute Cancer Immunology Dream Team Translational Research Grant [SU2C-AACR-DT1012]
- V Foundation-Gil Nickel Family Endowed Fellowship in Melanoma Research
- Spanish Society of Medical Oncology for Translational Research in reference centers
- Rio Ortega Scholarship from the Hospital 12 de Octubre, Madrid, Spain
- NIH [T32CA009120-36]
- Research Scholar Award from the American Cancer Society [RSG-12-257-01-TBE]
- NIH/National Center for Advancing Translational Science UCLA CTSI [UL1TR000124]
- Established Investigator Award from the Melanoma Research Alliance [20120279]
Purpose: To evaluate the immunomodulatory effects of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) blockade with tremelimumab in peripheral blood mononuclear cells (PBMC). Experimental Design: We used next-generation sequencing to study the complementarity-determining region 3 (CDR3) from the rearranged T-cell receptor (TCR) variable beta (V-beta) in PBMCs of 21 patients, at baseline and 30 to 60 days after receiving tremelimumab. Results: After receiving tremelimumab, there was a median of 30% increase in unique productive sequences of TCR V-beta CDR3 in 19 out of 21 patients, and a median decrease of 30% in only 2 out of 21 patients. These changes were significant for richness (P = 0.01) and for Shannon index diversity (P = 0.04). In comparison, serially collected PBMCs from four healthy donors did not show a significant change in TCR V-beta CDR3 diversity over 1 year. There was a significant difference in the total unique productive TCR V-beta CDR3 sequences between patients experiencing toxicity with tremelimumab compared with patients without toxicity (P = 0.05). No relevant differences were noted between clinical responders and nonresponders. Conclusions: CTLA4 blockade with tremelimumab diversifies the peripheral T-cell pool, representing a pharmacodynamic effect of how this class of antibodies modulates the human immune system.
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