Header

UZH-Logo

Maintenance Infos

Peripheral blood TCR repertoire profiling may facilitate patient stratification for immunotherapy against melanoma


Hogan, Sabrina A; Courtier, Anaïs; Cheng, Phil F; Jaberg-Bentele, Nicoletta F; Goldinger, Simone M; Manuel, Manuarii; Perez, Solène; Plantier, Nadia; Mouret, Jean-François; Nguyen-Kim, Thi Dan Linh; Raaijmakers, Marieke Mi; Kvistborg, Pia; Pasqual, Nicolas; Haanen, John B A G; Dummer, Reinhard; Levesque, Mitchell P (2019). Peripheral blood TCR repertoire profiling may facilitate patient stratification for immunotherapy against melanoma. Cancer Immunology Research, 7(1):77-85.

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 liquid biopsies 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 ROC 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 responses 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.

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 liquid biopsies 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 ROC 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 responses 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.

Statistics

Citations

Dimensions.ai Metrics

Altmetrics

Downloads

0 downloads since deposited on 13 Dec 2018
0 downloads since 12 months

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Diagnostic and Interventional Radiology
04 Faculty of Medicine > University Hospital Zurich > Dermatology Clinic
Dewey Decimal Classification:610 Medicine & health
Language:English
Date:1 January 2019
Deposited On:13 Dec 2018 09:21
Last Modified:20 Jan 2019 06:44
Publisher:American Association for Cancer Research
ISSN:2326-6066
Additional Information:European Union (EU), Horizon 2020
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1158/2326-6066.CIR-18-0136
PubMed ID:30425105
Project Information:
  • : FunderH2020
  • : Grant ID641458
  • : Project TitleMELanoma GENetics - understanding and biomarking the genetic and immunological determinants of melanoma survival

Download