Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors

• Published in: The Journal of clinical investigation 2019-05, Vol.129 (5), p.2056-2070
• Main Authors: Chen, Fangjun, Zou, Zhengyun, Du, Juan, Su, Shu, Shao, Jie, Meng, Fanyan, Yang, Ju, Xu, Qiuping, Ding, Naiqing, Yang, Yang, Liu, Qin, Wang, Qin, Sun, Zhichen, Zhou, Shujuan, Du, Shiyao, Wei, Jia, Liu, Baorui
• Format: Article
• Language: English
• Subjects: Adult; Aged; Antigens, Neoplasm - immunology; Biomedical research; Cancer; Cancer immunotherapy; Cancer metastasis; Cancer research; Cancer Vaccines - immunology; Care and treatment; Clinical Medicine; Computational Biology; Dendritic cells; Disease-Free Survival; Epitopes - immunology; Female; Gene frequency; Genomics; Histocompatibility antigen HLA; HLA-A2 Antigen - immunology; Humans; Immune response; Immune System; Immunogenicity; Immunologic Factors; Immunological memory; Immunophenotyping; Immunotherapy; Immunotherapy - methods; Inhibitory Concentration 50; Lymphocytes; Lymphocytes T; Male; Medical research; Melanoma; Memory cells; Metastases; Middle Aged; Mutation; Mutation hot spots; Neoantigens; Neoplasm Metastasis; Neoplasms - immunology; Neoplasms - therapy; Neural networks; Pancreatic cancer; Pancreatic Neoplasms - immunology; Patients; Peptides; Peptides - immunology; Phenotype; Polymerase Chain Reaction; Precision Medicine - methods; Solid tumors; T cells; T-Lymphocytes - immunology; Thymoma; Thymoma - immunology; Thymoma - metabolism; Translational Medical Research; Tumor antigens; Tumors; Young Adult
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI99538

Recent genomic and bioinformatic technological advances have made it possible to dissect the immune response to personalized neoantigens encoded by tumor-specific mutations. However, timely and efficient identification of neoantigens is still one of the major obstacles to using personalized neoantigen-based cancer immunotherapy. Two different pipelines of neoantigens identification were established in this study: (1) Clinical grade targeted sequencing was performed in patients with refractory solid tumor, and mutant peptides with high variant allele frequency and predicted high HLA-binding affinity were de novo synthesized. (2) An inventory-shared neoantigen peptide library of common solid tumors was constructed, and patients' hotspot mutations were matched to the neoantigen peptide library. The candidate neoepitopes were identified by recalling memory T-cell responses in vitro. Subsequently, neoantigen-loaded dendritic cell vaccines and neoantigen-reactive T cells were generated for personalized immunotherapy in six patients. Immunogenic neo-epitopes were recognized by autologous T cells in 3 of 4 patients who utilized the de novo synthesis mode and in 6 of 13 patients who performed shared neoantigen peptide library, respectively. A metastatic thymoma patient achieved a complete and durable response beyond 29 months after treatment. Immune-related partial response was observed in another patient with metastatic pancreatic cancer. The remaining four patients achieved the prolonged stabilization of disease with a median PFS of 8.6 months. The current study provided feasible pipelines for neoantigen identification. Implementing these strategies to individually tailor neoantigens could facilitate the neoantigen-based translational immunotherapy research.TRIAL REGSITRATION. ChiCTR.org ChiCTR-OIC-16010092, ChiCTR-OIC-17011275, ChiCTR-OIC-17011913; ClinicalTrials.gov NCT03171220. This work was funded by grants from the National Key Research and Development Program of China (Grant No. 2017YFC1308900), the National Major Projects for "Major New Drugs Innovation and Development" (Grant No.2018ZX09301048-003), the National Natural Science Foundation of China (Grant No. 81672367, 81572329, 81572601), and the Key Research and Development Program of Jiangsu Province (No. BE2017607).