TY - JOUR
T1 - CTLA4 blockade broadens the peripheral T-cell receptor repertoire
AU - Robert, Lidia
AU - Tsoi, Jennifer
AU - Wang, Xiaoyan
AU - Emerson, Ryan
AU - Homet, Blanca
AU - Chodon, Thinle
AU - Mok, Stephen
AU - Huang, Rong Rong
AU - Cochran, Alistair J.
AU - Comin-Anduix, Begoña
AU - Koya, Richard C.
AU - Graeber, Thomas G.
AU - Robins, Harlan
AU - Ribas, Antoni
PY - 2014/5/1
Y1 - 2014/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84899750907&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84899750907&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-13-2648
DO - 10.1158/1078-0432.CCR-13-2648
M3 - Article
C2 - 24583799
AN - SCOPUS:84899750907
SN - 1078-0432
VL - 20
SP - 2424
EP - 2432
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 9
ER -