Peripheral Blood TCR Repertoire Profiling May Facilitate Patient Stratification for Immunotherapy against Melanoma.

Abstract

Many metastatic melanoma patients experience durable responses to anti-PD1 and/or anti-CTLA4; however, a significant proportion (over 50%) do not benefit from the therapies. In this study, we sought to assess pretreatment liquid biopsies for biomarkers that may correlate with response to checkpoint blockade. We measured the combinatorial diversity evenness of the T-cell receptor (TCR) repertoire (the DE50, with low values corresponding to more clonality and lack of TCR diversity) in pretreatment peripheral blood mononuclear cells from melanoma patients treated with anti-CTLA4 (n = 42) or anti-PD1 (n = 38) using a multi-N-plex PCR assay on genomic DNA (gDNA). A receiver operating characteristic curve determined the optimal threshold for a dichotomized analysis according to objective responses as defined by RECIST1.1. Correlations between treatment outcome, clinical variables, and DE50 were assessed in multivariate regression models and confirmed with Fisher exact tests. In samples obtained prior to treatment initiation, we showed that low DE50 values were predictive of a longer progression-free survival and good responses to PD-1 blockade, but, on the other hand, predicted a poor response to CTLA4 inhibition. Multivariate logistic regression models identified DE50 as the only independent predictive factor for response to anti-CTLA4 therapy (P = 0.03) and anti-PD1 therapy (P = 0.001). Fisher exact tests confirmed the association of low DE50 with response in the anti-CTLA4 (P = 0.041) and the anti-PD1 cohort (P = 0.0016). Thus, the evaluation of basal TCR repertoire diversity in peripheral blood, using a PCR-based method, could help predict responses to anti-PD1 and anti-CTLA4 therapies.

• Authors: Sabrina A Hogan, Anaïs Courtier, Phil F Cheng, Nicoletta F Jaberg-Bentele, Simone M Goldinger, Manuarii Manuel, Solène Perez, Nadia Plantier, Jean-François Mouret, Thi Dan Linh Nguyen-Kim, Marieke I G Raaijmakers, Pia Kvistborg, Nicolas Pasqual, John B A G Haanen, Reinhard Dummer, Mitchell P Levesque
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 7 Issue 1 Pg. 77-85 (01 2019) ISSN: 2326-6074 [Electronic] United States
• PMID: 30425105 (Publication Type: Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Antibodies, Monoclonal, Humanized
• Antineoplastic Agents, Immunological
• CTLA-4 Antigen
• CTLA4 protein, human
• Ipilimumab
• PDCD1 protein, human
• Programmed Cell Death 1 Receptor
• Receptors, Antigen, T-Cell
• pembrolizumab

Topics

• Adult
• Aged
• Antibodies, Monoclonal, Humanized (therapeutic use)
• Antineoplastic Agents, Immunological (therapeutic use)
• CTLA-4 Antigen (antagonists & inhibitors)
• Female
• Humans
• Immunotherapy
• Ipilimumab (therapeutic use)
• Male
• Melanoma (drug therapy, immunology)
• Middle Aged
• Programmed Cell Death 1 Receptor (antagonists & inhibitors)
• Progression-Free Survival
• Receptors, Antigen, T-Cell (immunology)
• Skin Neoplasms (drug therapy, immunology)