title: CTLA4 blockade broadens the peripheral T-cell receptor repertoire.
abstract: OBJECTIVE
  To evaluate the immunomodulatory effects of cytotoxic T-lymphocyte-associated protein 4 (CTLA4) blockade with tremelimumab in peripheral blood mononuclear cells (PBMC).
  
  
  METHODS
  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.
authors.affiliation: Authors' Affiliations: Division of Hematology-Oncology, Department of Medicine, Departments of Molecular and Medical Pharmacology, Medicine Statistics core, and Pathology and Laboratory Medicine, Division of Surgical-Oncology, Department of Surgery, Jonsson Comprehensive Cancer Center, University of California at Los Angeles, Los Angeles, California; Fred Hutchinson Cancer Research Center; Adaptive Biotechnologies, Seattle, Washington; and Instituto de Salud Carlos III, Madrid, Spain.
authors.forename: Lidia
authors.initials: L
authors.lastname: Robert
authors.forename: Jennifer
authors.initials: J
authors.lastname: Tsoi
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Wang
authors.forename: Ryan
authors.initials: R
authors.lastname: Emerson
authors.forename: Blanca
authors.initials: B
authors.lastname: Homet
authors.forename: Thinle
authors.initials: T
authors.lastname: Chodon
authors.forename: Stephen
authors.initials: S
authors.lastname: Mok
authors.forename: Rong Rong
authors.initials: RR
authors.lastname: Huang
authors.forename: Alistair J
authors.initials: AJ
authors.lastname: Cochran
authors.forename: Begoña
authors.initials: B
authors.lastname: Comin-Anduix
authors.forename: Richard C
authors.initials: RC
authors.lastname: Koya
authors.forename: Thomas G
authors.initials: TG
authors.lastname: Graeber
authors.forename: Harlan
authors.initials: H
authors.lastname: Robins
authors.forename: Antoni
authors.initials: A
authors.lastname: Ribas
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D060908:CTLA-4 Antigen / Q000037:antagonists & inhibitors*; D016000:Cluster Analysis; D022801:Complementarity Determining Regions / Q000235:genetics; D019295:Computational Biology; D005260:Female; D014644:Genetic Variation; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000378:metabolism; D018655:Lymphocyte Count; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008545:Melanoma / Q000175:diagnosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000401:mortality; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000235:genetics; D017422:Sequence Analysis, DNA; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D060908:CTLA-4 Antigen; D022801:Complementarity Determining Regions; D011948:Receptors, Antigen, T-Cell; D016693:Receptors, Antigen, T-Cell, alpha-beta; C520704:tremelimumab