Data from CTLA4 Blockade Broadens the Peripheral T-Cell Receptor Repertoire

Abstract

<div>Abstract<p><b>Purpose:</b> To evaluate the immunomodulatory effects of cytotoxic T–lymphocyte-associated protein 4 (CTLA4) blockade with tremelimumab in peripheral blood mononuclear cells (PBMC).</p><p><b>Experimental Design:</b> 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.</p><p><b>Results:</b> 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 (<i>P</i> = 0.01) and for Shannon index diversity (<i>P</i> = 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 (<i>P</i> = 0.05). No relevant differences were noted between clinical responders and nonresponders.</p><p><b>Conclusions:</b> 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. <i>Clin Cancer Res; 20(9); 2424–32. ©2014 AACR</i>.</p></div>