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.

Biogem Scarl Institute of Genetic Research Laboratory of Precision and Molecular Oncology Ariano Irpino Avellino Italy

Central European Institute of Technology University of Veterinary and Pharmaceutical Sciences Brno Czech Republic

Department of Biophysics 2nd Faculty of Medicine Charles University Prague Prague Czech Republic

Department of Medical Biotechnology University of Siena Siena Italy

Department of Precision Medicine University of Campania L Vanvitelli Naples Italy

Medical and Translational Oncology Unit Department of Experimental and Clinical Medicine Magna Graecia University Catanzaro Italy

Medical Oncology Unit Grand Metropolitan Hospital Bianchi Melacrino Morelli Reggio Calabria Italy

Radiotherapy Unit Ospedale del Mare ASL Napoli 1 Naples Italy

Regina Elena National Cancer Institute IRCCS Rome Italy

Sbarro Institute for Cancer Research and Molecular Medicine and Center of Biotechnology College of Science and Technology Temple University Philadelphia Pennsylvania USA

Section of Radiation Oncology Medical School University of Siena Siena Italy

Tissue Typing Unit Grand Metropolitan Hospital Bianchi Melacrino Morelli Reggio Calabria Italy

Unit of Pharmacy Grand Metropolitan Hospital Bianchi Melacrino Morelli Reggio Calabria Italy

Zobrazit více v PubMed

Pilkington G, Boland A, Brown T, et al. . A systematic review of the clinical effectiveness of first-line chemotherapy for adult patients with locally advanced or metastatic non-small cell lung cancer. Thorax 2015;70:359–67. 10.1136/thoraxjnl-2014-205914 PubMed DOI

Hirsch FR, Scagliotti GV, Mulshine JL, et al. . Lung cancer: current therapies and new targeted treatments. Lancet 2017;389:299–311. 10.1016/S0140-6736(16)30958-8 PubMed DOI

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer 2012;12:252–64. 10.1038/nrc3239 PubMed DOI PMC

Horn L, Spigel DR, Vokes EE, et al. . Nivolumab versus docetaxel in previously treated patients with advanced non-small-cell lung cancer: two-year outcomes from two randomized, open-label, phase III trials (CheckMate 017 and CheckMate 057). J Clin Oncol 2017;35:3924–33. 10.1200/JCO.2017.74.3062 PubMed DOI PMC

Xia L, Liu Y, Wang Y. PD‐1/PD‐L1 blockade therapy in advanced Non‐Small‐Cell lung cancer: current status and future directions. Oncologist 2019;24:31–41. 10.1634/theoncologist.2019-IO-S1-s05 PubMed DOI PMC

Day D, Hansen AR. Immune-Related adverse events associated with immune checkpoint inhibitors. BioDrugs 2016;30:571–84. 10.1007/s40259-016-0204-3 PubMed DOI

Weber JS, Yang JC, Atkins MB, et al. . Toxicities of immunotherapy for the practitioner. J Clin Oncol 2015;33:2092–9. 10.1200/JCO.2014.60.0379 PubMed DOI PMC

Topalian SL, Taube JM, Anders RA, et al. . Mechanism-Driven biomarkers to guide immune checkpoint blockade in cancer therapy. Nat Rev Cancer 2016;16:275–87. 10.1038/nrc.2016.36 PubMed DOI PMC

Wölfel T, Klehmann E, Müller C, et al. . Lysis of human melanoma cells by autologous cytolytic T cell clones. Identification of human histocompatibility leukocyte antigen A2 as a restriction element for three different antigens. J Exp Med 1989;170:797–810. 10.1084/jem.170.3.797 PubMed DOI PMC

Hunt DF, Henderson RA, Shabanowitz J, et al. . Characterization of peptides bound to the class I MHC molecule HLA-A2.1 by mass spectrometry. Science 1992;255:1261–3. 10.1126/science.1546328 PubMed DOI

Crowley NJ, Darrow TL, Quinn-Allen MA, et al. . MHC-restricted recognition of autologous melanoma by tumor-specific cytotoxic T cells. Evidence for restriction by a dominant HLA-A allele. J Immunol 1991;146:1692–9. PubMed

McDonnell AM, Robinson BWS, Currie AJ. Tumor antigen cross-presentation and the dendritic cell: where it all begins? Clin Dev Immunol 2010;2010:1–9. 10.1155/2010/539519 PubMed DOI PMC

Simmonds MJ, Gough SCL. Genetic insights into disease mechanisms of autoimmunity. Br Med Bull 2004;71:93–113. 10.1093/bmb/ldh032 PubMed DOI

Seymour L, Bogaerts J, Perrone A, et al. . iRECIST: guidelines for response criteria for use in trials testing immunotherapeutics. Lancet Oncol 2017;18:e143–52. 10.1016/S1470-2045(17)30074-8 PubMed DOI PMC

Guasp P, Lorente E, Martín-Esteban A, et al. . Redundancy and complementarity between ERAP1 and ERAP2 revealed by their effects on the Behcet's disease-associated HLA-B*51 peptidome. Mol Cell Proteomics 2019;18:1491–510. 10.1074/mcp.RA119.001515 PubMed DOI PMC

Chowell D, Morris LGT, Grigg CM, et al. . Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science 2018;359:582–7. 10.1126/science.aao4572 PubMed DOI PMC

Tran E, Robbins PF, Lu Y-C, et al. . T-Cell transfer therapy targeting mutant KRAS in cancer. N Engl J Med 2016;375:2255–62. 10.1056/NEJMoa1609279 PubMed DOI PMC

Das S, Johnson DB. Immune-Related adverse events and anti-tumor efficacy of immune checkpoint inhibitors. J Immunother Cancer 2019;7:306. 10.1186/s40425-019-0805-8 PubMed DOI PMC

Nunes JM, Buhler S, Roessli D, et al. . The HLA-net GENE[RATE] pipeline for effective HLA data analysis and its application to 145 population samples from Europe and neighbouring areas. Tissue Antigens 2014;83:307–23. 10.1111/tan.12356 PubMed DOI

Mangalam AK, Taneja V, David CS. Hla class II molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile. J Immunol 2013;190:513–9. 10.4049/jimmunol.1201891 PubMed DOI PMC

Gregersen PK, Silver J, Winchester RJ. The shared epitope hypothesis. An approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis. Arthritis Rheum 1987;30:1205–13. 10.1002/art.1780301102 PubMed DOI

Negrao MV, Lam VK, Reuben A, et al. . Pd-L1 expression, tumor mutational burden, and cancer gene mutations are stronger predictors of benefit from immune checkpoint blockade than HLA class I genotype in non-small cell lung cancer. J Thorac Oncol 2019;14:1021–31. 10.1016/j.jtho.2019.02.008 PubMed DOI

Giannicola R, D'Arrigo G, Botta C, et al. . Early blood rise in auto-antibodies to nuclear and smooth muscle antigens is predictive of prolonged survival and autoimmunity in metastatic-non-small cell lung cancer patients treated with PD-1 immune-check point blockade by nivolumab. Mol Clin Oncol 2019;11:81–90. 10.3892/mco.2019.1859 PubMed DOI PMC

Attia P, Phan GQ, Maker AV, et al. . Autoimmunity correlates with tumor regression in patients with metastatic melanoma treated with anti-cytotoxic T-lymphocyte antigen-4. J Clin Oncol 2005;23:6043–53. 10.1200/JCO.2005.06.205 PubMed DOI PMC

Wang W, Green M, Rebecca Liu J. CD8+ T Cells in Immunotherapy, Radiotherapy, and Chemotherapy : Zitvogel L, Kroemer G, Oncoimmunology: a practical guide for cancer immunotherapy. Cham: Springer International Publishing, 2018: 23–39.

Kumar P, Bhattacharya P, Prabhakar BS. A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity. J Autoimmun 2018;95:77–99. 10.1016/j.jaut.2018.08.007 PubMed DOI PMC

Gross G, Margalit A. Targeting tumor-associated antigens to the MHC class I presentation pathway. Endocr Metab Immune Disord Drug Targets 2007;7:99–109. 10.2174/187153007780832064 PubMed DOI

Falk K, Rötzschke O, Stevanović S, et al. . Allele-Specific motifs revealed by sequencing of self-peptides eluted from MHC molecules. Nature 1991;351:290–6. 10.1038/351290a0 PubMed DOI

Parker KC, Bednarek MA, Coligan JE. Scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. J Immunol 1994;152:163–75. PubMed

Rammensee H, Bachmann J, Emmerich NP, et al. . SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 1999;50:213–9. 10.1007/s002510050595 PubMed DOI

Parmiani G, Russo V, Maccalli C, et al. . Peptide-Based vaccines for cancer therapy. Hum Vaccin Immunother 2014;10:3175–8. 10.4161/hv.29418 PubMed DOI PMC

Correale P, Botta C, Ciliberto D, et al. . Immunotherapy of colorectal cancer: new perspectives after a long path. Immunotherapy 2016;8:1281–92. 10.2217/imt-2016-0089 PubMed DOI

Correale P, Walmsley K, Nieroda C, et al. . In vitro generation of human cytotoxic T lymphocytes specific for peptides derived from prostate-specific antigen. J Natl Cancer Inst 1997;89:293–300. 10.1093/jnci/89.4.293 PubMed DOI

Tsang KY, Zhu M, Nieroda CA, et al. . Phenotypic stability of a cytotoxic T-cell line directed against an immunodominant epitope of human carcinoembryonic antigen. Clin Cancer Res 1997;3:2439–49. PubMed

Cusi MG, Botta C, Pastina P, et al. . Phase I trial of thymidylate synthase poly-epitope peptide (TSPP) vaccine in advanced cancer patients. Cancer Immunol Immunother 2015;64:1159–73. 10.1007/s00262-015-1711-7 PubMed DOI PMC

Correale P, Botta C, Martino EC, et al. . Phase Ib study of poly-epitope peptide vaccination to thymidylate synthase (TSPP) and GOLFIG chemo-immunotherapy for treatment of metastatic colorectal cancer patients. Oncoimmunology 2016;5:e1101205. 10.1080/2162402X.2015.1101205 PubMed DOI PMC

Correale P, Botta C, Staropoli N, et al. . Systemic inflammatory status predict the outcome of K-ras WT metastatic colorectal cancer patients receiving the thymidylate synthase poly-epitope-peptide anticancer vaccine. Oncotarget 2018;9:20539–54. 10.18632/oncotarget.24993 PubMed DOI PMC

Kotsakis A, Vetsika E-K, Christou S, et al. . Clinical outcome of patients with various advanced cancer types vaccinated with an optimized cryptic human telomerase reverse transcriptase (TERT) peptide: results of an expanded phase II study. Ann Oncol 2012;23:442–9. 10.1093/annonc/mdr396 PubMed DOI

Chowell D, Krishna C, Pierini F, et al. . Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. Nat Med 2019;25:1715–20. 10.1038/s41591-019-0639-4 PubMed DOI PMC

Seliger B, Ferrone S. Hla class I antigen processing machinery defects in cancer Cells-Frequency, functional significance, and clinical relevance with special emphasis on their role in T cell-based immunotherapy of malignant disease. Methods Mol Biol 2055;2020:325–50. PubMed

Respa A, Bukur J, Ferrone S, et al. . Association of IFN-gamma signal transduction defects with impaired HLA class I antigen processing in melanoma cell lines. Clin Cancer Res 2011;17:2668–78. 10.1158/1078-0432.CCR-10-2114 PubMed DOI PMC

Trefny MP, Rothschild SI, Uhlenbrock F, et al. . A variant of a killer cell immunoglobulin-like receptor is associated with resistance to PD-1 blockade in lung cancer. Clin Cancer Res 2019;25:3026–34. 10.1158/1078-0432.CCR-18-3041 PubMed DOI

Ackermann CJ, Reck M, Paz-Ares L, et al. . First-Line immune checkpoint blockade for advanced non-small-cell lung cancer: travelling at the speed of light. Lung Cancer 2019;134:245–53. 10.1016/j.lungcan.2019.06.007 PubMed DOI

Mulkey F, By K, Theoret MR, et al. . Analysis of early mortality in randomized clinical trials evaluating anti-PD-1/PD-L1 antibodies: a systematic analysis by the United States food and drug administration (FDA). JCO 2019;37:2516 10.1200/JCO.2019.37.15_suppl.2516 DOI