A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results.

Journal

Nature medicine

ISSN: 1546-170X

Titre abrégé: Nat Med

Pays: United States

ID NLM: 9502015

Informations de publication

Date de publication:
Apr 2024

Historique:

received: 11 10 2023

accepted: 29 01 2024

pubmed: 28 3 2024

medline: 28 3 2024

entrez: 28 3 2024

Statut: ppublish

Résumé

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .

Identifiants

DOI: 10.1038/s41591-024-02851-9 PMID: 38538867

pubmed: 38538867

doi: 10.1038/s41591-024-02851-9

pii: 10.1038/s41591-024-02851-9

doi:

Banques de données

ClinicalTrials.gov

['NCT03953235']

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

Pagination

1013-1022

Informations de copyright

Références

Keenan, T. E., Burke, K. P. & Van Allen, E. M. Genomic correlates of response to immune checkpoint blockade. Nat. Med. 25, 389–402 (2019).

doi: 10.1038/s41591-019-0382-x pubmed: 30842677 pmcid: 6599710

Rizvi, N. A. et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).

doi: 10.1126/science.aaa1348 pubmed: 25765070 pmcid: 4993154

Palmer, C. D. et al. Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine for advanced metastatic solid tumors: phase 1 trial interim results. Nat. Med. 28, 1619–1629 (2022).

doi: 10.1038/s41591-022-01937-6 pubmed: 35970920

Prior, I. A., Hood, F. E. & Hartley, J. L. The frequency of Ras mutations in cancer. Cancer Res. 80, 2969–2974 (2020).

doi: 10.1158/0008-5472.CAN-19-3682 pubmed: 32209560 pmcid: 7367715

Hong, D. S. et al. KRAS

doi: 10.1056/NEJMoa1917239 pubmed: 32955176 pmcid: 7571518

Jänne, P. A. et al. Adagrasib in non-small cell lung cancer harboring a KRAS

doi: 10.1056/NEJMoa2204619 pubmed: 35658005

Kim, D., Xue, J. Y. & Lito, P. Targeting KRAS

doi: 10.1016/j.cell.2020.09.044 pubmed: 33065029 pmcid: 7669705

Skoulidis, F. et al. Sotorasib for lung cancers with KRAS

doi: 10.1056/NEJMoa2103695 pubmed: 34096690 pmcid: 9116274

Awad, M. M. et al. Acquired resistance to KRAS

doi: 10.1056/NEJMoa2105281 pubmed: 34161704 pmcid: 8864540

Canon, J. et al. The clinical KRAS

doi: 10.1038/s41586-019-1694-1 pubmed: 31666701

Bulik-Sullivan, B. et al. Deep learning using tumor HLA peptide mass spectrometry datasets improves neoantigen identification. Nat. Biotechnol. 37, 55–63 (2019).

doi: 10.1038/nbt.4313

Fourcade, J. et al. PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8

doi: 10.1158/0008-5472.CAN-13-2908 pubmed: 24343228

Tran, E. et al. T cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375, 2255–2262 (2016).

doi: 10.1056/NEJMoa1609279 pubmed: 27959684 pmcid: 5178827

Maiers, M., Gragert, L. & Klitz, W. High-resolution HLA alleles and haplotypes in the United States population. Hum. Immunol. 68, 779–788 (2007).

doi: 10.1016/j.humimm.2007.04.005 pubmed: 17869653

Cerami, E. et al. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2, 401–404 (2012).

doi: 10.1158/2159-8290.CD-12-0095 pubmed: 22588877

de Bruijn, I. et al. Analysis and visualization of longitudinal genomic and clinical data from the AACR Project GENIE Biopharma Collaborative in cBioPortal. Cancer Res. 83, 3861–3867 (2023).

doi: 10.1158/0008-5472.CAN-23-0816 pubmed: 37668528 pmcid: 10690089

Gao, J. et al. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6, pl1 (2013).

doi: 10.1126/scisignal.2004088 pubmed: 23550210 pmcid: 4160307

Guo, W., Wang, S. J., Yang, S., Lynn, H. & Ji, Y. A Bayesian interval dose-finding design addressing Ockham’s razor: mTPI-2. Contemp. Clin. Trials 58, 23–33 (2017).

doi: 10.1016/j.cct.2017.04.006 pubmed: 28458054

Ji, Y. & Wang, S. J. Modified toxicity probability interval design: a safer and more reliable method than the 3 + 3 design for practical phase I trials. J. Clin. Oncol. 31, 1785–1791 (2013).

doi: 10.1200/JCO.2012.45.7903 pubmed: 23569307 pmcid: 3641699

Ramos-Casals, M. et al. Immune-related adverse events of checkpoint inhibitors. Nat. Rev. Dis. Prim. 6, 38 (2020).

doi: 10.1038/s41572-020-0160-6 pubmed: 32382051

Vega, D. M. et al. Changes in circulating tumor DNA reflect clinical benefit across multiple studies of patients with non-small-cell lung cancer treated with immune checkpoint inhibitors. JCO Precis. Oncol. 6, e2100372 (2022).

doi: 10.1200/PO.21.00372 pubmed: 35952319 pmcid: 9384957

Bratman, S. V. et al. Personalized circulating tumor DNA analysis as a predictive biomarker in solid tumor patients treated with pembrolizumab. Nat. Cancer 1, 873–881 (2020).

doi: 10.1038/s43018-020-0096-5 pubmed: 35121950

Sivapalan L. et al. Liquid biopsy approaches to capture tumor evolution and clinical outcomes during cancer immunotherapy. J. Immunother. Cancer https://doi.org/10.1136/jitc-2022-005924 (2023).

Assaf, Z. J. F. et al. A longitudinal circulating tumor DNA-based model associated with survival in metastatic non-small-cell lung cancer. Nat. Med. 29, 859–868 (2023).

doi: 10.1038/s41591-023-02226-6 pubmed: 36928816 pmcid: 10115641

Gettinger, S. et al. Impaired HLA class I antigen processing and presentation as a mechanism of acquired resistance to immune checkpoint inhibitors in lung cancer. Cancer Discov. 7, 1420–1435 (2017).

doi: 10.1158/2159-8290.CD-17-0593 pubmed: 29025772 pmcid: 5718941

Schoenfeld, A. J. & Hellmann, M. D. Acquired resistance to immune checkpoint inhibitors. Cancer Cell 37, 443–455 (2020).

doi: 10.1016/j.ccell.2020.03.017 pubmed: 32289269 pmcid: 7182070

Rodriguez, F., Harkins, S., Slifka, M. K. & Whitton, J. L. Immunodominance in virus-induced CD8

doi: 10.1128/JVI.76.9.4251-4259.2002 pubmed: 11932390 pmcid: 155093

Carbone, D. P. et al. Immunization with mutant p53- and K-Ras-derived peptides in cancer patients: immune response and clinical outcome. J. Clin. Oncol. 23, 5099–5107 (2005).

doi: 10.1200/JCO.2005.03.158 pubmed: 15983396

Folegatti, P. M. et al. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet 396, 467–478 (2020).

doi: 10.1016/S0140-6736(20)31604-4 pubmed: 32702298 pmcid: 7445431

Shaw, A. R. & Suzuki, M. Immunology of adenoviral vectors in cancer therapy. Mol. Ther. Methods Clin. Dev. 15, 418–429 (2019).

doi: 10.1016/j.omtm.2019.11.001 pubmed: 31890734 pmcid: 6909129

Ogwang, C. et al. Prime-boost vaccination with chimpanzee adenovirus and modified vaccinia Ankara encoding TRAP provides partial protection against Plasmodium falciparum infection in Kenyan adults. Sci. Transl. Med. 7, 286re5 (2015).

doi: 10.1126/scitranslmed.aaa2373 pubmed: 25947165 pmcid: 4687051

Schreiber, H., Wu, T. H., Nachman, J. & Kast, W. M. Immunodominance and tumor escape. Semin. Cancer Biol. 12, 25–31 (2002).

doi: 10.1006/scbi.2001.0401 pubmed: 11926408

Burger, M. L. et al. Antigen dominance hierarchies shape TCF1

doi: 10.1016/j.cell.2021.08.020 pubmed: 34534464 pmcid: 8522630

Friedman, J. et al. Neoadjuvant PD-1 immune checkpoint blockade reverses functional immunodominance among tumor antigen-specific T cells. Clin. Cancer Res. 26, 679–689 (2020).

doi: 10.1158/1078-0432.CCR-19-2209 pubmed: 31645352

Moodie, Z. et al. Response definition criteria for ELISPOT assays revisited. Cancer Immunol. Immunother. 59, 1489–1501 (2010).

doi: 10.1007/s00262-010-0875-4 pubmed: 20549207 pmcid: 2909425

Janetzki, S. et al. Guidelines for the automated evaluation of Elispot assays. Nat. Protoc. 10, 1098–1115 (2015).

doi: 10.1038/nprot.2015.068 pubmed: 26110715

USE (Universal Spectrum Explorer). ProteomicsDB https://www.proteomicsdb.org/use/ (2021).

Lai, Z. et al. VarDict: a novel and versatile variant caller for next-generation sequencing in cancer research. Nucleic Acids Res. 44, e108 (2016).

doi: 10.1093/nar/gkw227 pubmed: 27060149 pmcid: 4914105