Background Nivolumab is a human monoclonal antibody against programmed cell death receptor-1 (PD-1) able to rescue quiescent tumor infiltrating cytotoxic T lymphocytes (CTLs) restoring their ability to kill target cells expressing specific tumor antigen-derived epitope peptides bound to homologue human leukocyte antigen (HLA) molecules. Nivolumab is currently an active but expensive therapeutic agent for metastatic non-small cell lung cancer (mNSCLC), producing, in some cases, immune-related adverse events (irAEs). At the present, no reliable biomarkers have been validated to predict either treatment response or adverse events in treated patients. Methods We performed a retrospective multi-institutional analysis including 119 patients with mNSCLC who received PD-1 blockade since November 2015 to investigate the predictive role of germinal class I HLA and DRB1 genotype. We investigated the correlation among patients' outcome and irAEs frequency with specific HLA A, B, C and DRB1 alleles by reverse sequence-specific oligonucleotide (SSO) DNA typing. Results A poor outcome in patients negative for the expression of two most frequent HLA-A alleles was detected (HLA: HLA-A∗01 and or A∗02; progression-free survival (PFS): 7.5 (2.8 to 12.2) vs 15.9 (0 to 39.2) months, p=0.01). In particular, HLA-A∗01-positive patients showed a prolonged PFS of 22.6 (10.2 to 35.0) and overall survival (OS) of 30.8 (7.7 to 53.9) months, respectively. We also reported that HLA-A and DRB1 locus heterozygosis (het) were correlated to a worse OS if we considered het in the locus A; in reverse, long survival was correlated to het in DRB1. Conclusions This study demonstrate that class I and II HLA allele characterization to define tumor immunogenicity has relevant implications in predicting nivolumab efficacy in mNSCLC and provide the rationale for further prospective trials of cancer immunotherapy.

Distinctive germline expression of class i human leukocyte antigen (HLA) alleles and DRB1 heterozygosis predict the outcome of patients with non-small cell lung cancer receiving PD-1/PD-L1 immune checkpoint blockade

Nardone V.;Luce A.;Caraglia M.;
2020

Abstract

Background Nivolumab is a human monoclonal antibody against programmed cell death receptor-1 (PD-1) able to rescue quiescent tumor infiltrating cytotoxic T lymphocytes (CTLs) restoring their ability to kill target cells expressing specific tumor antigen-derived epitope peptides bound to homologue human leukocyte antigen (HLA) molecules. Nivolumab is currently an active but expensive therapeutic agent for metastatic non-small cell lung cancer (mNSCLC), producing, in some cases, immune-related adverse events (irAEs). At the present, no reliable biomarkers have been validated to predict either treatment response or adverse events in treated patients. Methods We performed a retrospective multi-institutional analysis including 119 patients with mNSCLC who received PD-1 blockade since November 2015 to investigate the predictive role of germinal class I HLA and DRB1 genotype. We investigated the correlation among patients' outcome and irAEs frequency with specific HLA A, B, C and DRB1 alleles by reverse sequence-specific oligonucleotide (SSO) DNA typing. Results A poor outcome in patients negative for the expression of two most frequent HLA-A alleles was detected (HLA: HLA-A∗01 and or A∗02; progression-free survival (PFS): 7.5 (2.8 to 12.2) vs 15.9 (0 to 39.2) months, p=0.01). In particular, HLA-A∗01-positive patients showed a prolonged PFS of 22.6 (10.2 to 35.0) and overall survival (OS) of 30.8 (7.7 to 53.9) months, respectively. We also reported that HLA-A and DRB1 locus heterozygosis (het) were correlated to a worse OS if we considered het in the locus A; in reverse, long survival was correlated to het in DRB1. Conclusions This study demonstrate that class I and II HLA allele characterization to define tumor immunogenicity has relevant implications in predicting nivolumab efficacy in mNSCLC and provide the rationale for further prospective trials of cancer immunotherapy.
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Utilizza questo identificativo per citare o creare un link a questo documento: http://hdl.handle.net/11591/432497
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