Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial.
Journal
Nature medicine
ISSN: 1546-170X
Titre abrégé: Nat Med
Pays: United States
ID NLM: 9502015
Informations de publication
Date de publication:
Apr 2024
Apr 2024
Historique:
received:
28
12
2022
accepted:
01
03
2024
pubmed:
8
4
2024
medline:
8
4
2024
entrez:
7
4
2024
Statut:
ppublish
Résumé
Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results from a single-arm, open-label, phase 1/2 study of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced HCC previously treated with a multityrosine kinase inhibitor. Safety and immunogenicity were assessed as primary endpoints, and treatment efficacy and feasibility were evaluated as secondary endpoints. The most common treatment-related adverse events were injection-site reactions, observed in 15 of 36 (41.6%) patients. No dose-limiting toxicities or treatment-related grade ≥3 events were observed. The objective response rate (modified intention-to-treat) per Response Evaluation Criteria in Solid Tumors 1.1 was 30.6% (11 of 36 patients), with 8.3% (3 of 36) of patients achieving a complete response. Clinical responses were associated with the number of neoantigens encoded in the vaccine. Neoantigen-specific T cell responses were confirmed in 19 of 22 (86.4%) evaluable patients by enzyme-linked immunosorbent spot assays. Multiparametric cellular profiling revealed active, proliferative and cytolytic vaccine-specific CD4
Identifiants
pubmed: 38584166
doi: 10.1038/s41591-024-02894-y
pii: 10.1038/s41591-024-02894-y
doi:
Banques de données
ClinicalTrials.gov
['NCT04251117']
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
1044-1053Informations de copyright
© 2024. The Author(s).
Références
Llovet, J. M. et al. Hepatocellular carcinoma. Nat. Rev. Dis. Primers 7, 6 (2021).
pubmed: 33479224
doi: 10.1038/s41572-020-00240-3
Cancer Facts & Figures 2022 www.cancer.org/content/dam/cancer-org/research/cancer-facts-and-statistics/annual-cancer-facts-and-figures/2022/2022-cancer-facts-and-figures.pdf (American Cancer Society, 2022).
Yarchoan, M. et al. PD-L1 expression and tumor mutational burden are independent biomarkers in most cancers. JCI Insight 4, e126908 (2019).
pubmed: 30895946
pmcid: 6482991
doi: 10.1172/jci.insight.126908
Desai, J. et al. Phase IA/IB study of single-agent tislelizumab, an investigational anti-PD-1 antibody, in solid tumors. J. Immunother. Cancer 8, e000453 (2020).
pubmed: 32540858
pmcid: 7295442
doi: 10.1136/jitc-2019-000453
Yau, T. et al. Nivolumab versus sorafenib in advanced hepatocellular carcinoma (CheckMate 459): a randomised, multicentre, open-label, phase 3 trial. Lancet Oncol. 23, 77–90 (2022).
pubmed: 34914889
doi: 10.1016/S1470-2045(21)00604-5
Finn, R. S. et al. Pembrolizumab as second-line therapy in patients with advanced hepatocellular carcinoma in KEYNOTE-240: a randomized, double-blind, phase III trial. J. Clin. Oncol. 38, 193–202 (2020).
pubmed: 31790344
doi: 10.1200/JCO.19.01307
Kudo, M. et al. Updated efficacy and safety of KEYNOTE-224: a phase II study of pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib. Eur. J. Cancer 167, 1–12 (2022).
pubmed: 35364421
doi: 10.1016/j.ejca.2022.02.009
Qin, S. et al. Pembrolizumab plus best supportive care versus placebo plus best supportive care as second-line therapy in patients in Asia with advanced hepatocellular carcinoma (HCC): phase 3 KEYNOTE-394 study. J. Clin. Oncol. 40, 383 (2022).
doi: 10.1200/JCO.2022.40.4_suppl.383
Zhu, A. X. et al. Pembrolizumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib (KEYNOTE-224): a non-randomised, open-label phase 2 trial. Lancet Oncol. 19, 940–952 (2018).
pubmed: 29875066
doi: 10.1016/S1470-2045(18)30351-6
Qin, S. et al. Tislelizumab vs sorafenib as first-line treatment for unresectable hepatocellular carcinoma: a phase 3 randomized clinical trial. JAMA Oncol. 9, 1651–1659 (2023).
pubmed: 37796513
pmcid: 10557031
doi: 10.1001/jamaoncol.2023.4003
Yarchoan, M., Johnson, B. A. 3rd, Lutz, E. R., Laheru, D. A. & Jaffee, E. M. Targeting neoantigens to augment antitumour immunity. Nat. Rev. Cancer 17, 209–222 (2017).
pubmed: 28233802
pmcid: 5575801
doi: 10.1038/nrc.2016.154
Blass, E. & Ott, P. A. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. Nat. Rev. Clin. Oncol. 18, 215–229 (2021).
pubmed: 33473220
pmcid: 7816749
doi: 10.1038/s41571-020-00460-2
Hu, Z., Ott, P. A. & Wu, C. J. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat. Rev. Immunol. 18, 168–182 (2018).
pubmed: 29226910
doi: 10.1038/nri.2017.131
McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).
pubmed: 26940869
pmcid: 4984254
doi: 10.1126/science.aaf1490
Castle, J. C. et al. Exploiting the mutanome for tumor vaccination. Cancer Res. 72, 1081–1091 (2012).
pubmed: 22237626
doi: 10.1158/0008-5472.CAN-11-3722
Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).
pubmed: 25901682
pmcid: 4838069
doi: 10.1038/nature14426
Gubin, M. M. et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature 515, 577–581 (2014).
pubmed: 25428507
pmcid: 4279952
doi: 10.1038/nature13988
Duperret, E. K. et al. A synthetic DNA, multi-neoantigen vaccine drives predominately MHC class I CD8
pubmed: 30679156
pmcid: 6622455
doi: 10.1158/2326-6066.CIR-18-0283
Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).
pubmed: 28678778
pmcid: 5577644
doi: 10.1038/nature22991
Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).
pubmed: 30568305
doi: 10.1038/s41586-018-0792-9
Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).
pubmed: 28678784
doi: 10.1038/nature23003
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).
pubmed: 35970920
doi: 10.1038/s41591-022-01937-6
Weber, J. S. et al. Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b study. Lancet 403, 632–644 (2024).
pubmed: 38246194
doi: 10.1016/S0140-6736(23)02268-7
Bhojnagarwala, P. S., Perales-Puchalt, A., Cooch, N., Sardesai, N. Y. & Weiner, D. B. A synDNA vaccine delivering neoAg collections controls heterogenous, multifocal murine lung and ovarian tumors via robust T cell generation. Mol. Ther. Oncolytics 21, 278–287 (2021).
pubmed: 34141866
pmcid: 8166642
doi: 10.1016/j.omto.2021.04.005
Kalams, S. A. et al. Safety and comparative immunogenicity of an HIV-1 DNA vaccine in combination with plasmid interleukin 12 and impact of intramuscular electroporation for delivery. J. Infect. Dis. 208, 818–829 (2013).
pubmed: 23840043
pmcid: 3733506
doi: 10.1093/infdis/jit236
Kalams, S. A. et al. Safety and immunogenicity of an HIV-1 gag DNA vaccine with or without IL-12 and/or IL-15 plasmid cytokine adjuvant in healthy, HIV-1 uninfected adults. PLoS ONE 7, e29231 (2012).
pubmed: 22242162
pmcid: 3252307
doi: 10.1371/journal.pone.0029231
Abou-Alfa, G. K. et al. Tremelimumab plus durvalumab in unresectable hepatocellular carcinoma. NEJM Evid. 1, EVIDoa2100070 (2022).
pubmed: 38319892
doi: 10.1056/EVIDoa2100070
Finn, R. S. et al. Results of KEYNOTE-240: phase 3 study of pembrolizumab (Pembro) vs best supportive care (BSC) for second line therapy in advanced hepatocellular carcinoma (HCC). J. Clin. Oncol. 37, 4004 (2019).
doi: 10.1200/JCO.2019.37.15_suppl.4004
Zhang, Q. et al. Prognostic and predictive impact of circulating tumor DNA in patients with advanced cancers treated with immune checkpoint blockade. Cancer Discov. 10, 1842–1853 (2020).
pubmed: 32816849
pmcid: 8358981
doi: 10.1158/2159-8290.CD-20-0047
Zhu, A. X. et al. Molecular correlates of clinical response and resistance to atezolizumab in combination with bevacizumab in advanced hepatocellular carcinoma. Nat. Med. 28, 1599–1611 (2022).
pubmed: 35739268
doi: 10.1038/s41591-022-01868-2
Neely, J. et al. Abstract 2145. Genomic and transcriptomic analyses related to the clinical efficacy of first-line nivolumab in advanced hepatocellular carcinoma from the phase 3 CheckMate 459 trial. Cancer Res. 82, 2145 (2022).
doi: 10.1158/1538-7445.AM2022-2145
Robert, L. et al. Distinct immunological mechanisms of CTLA-4 and PD-1 blockade revealed by analyzing TCR usage in blood lymphocytes. Oncoimmunology 3, e29244 (2014).
pubmed: 25083336
pmcid: 4108466
doi: 10.4161/onci.29244
Gangaev, A. et al. Differential effects of PD-1 and CTLA-4 blockade on the melanoma-reactive CD8 T cell response. Proc. Natl Acad. Sci. USA 118, e2102849118 (2021).
pubmed: 34670835
pmcid: 8639378
doi: 10.1073/pnas.2102849118
Szabo, P. A. et al. Single-cell transcriptomics of human T cells reveals tissue and activation signatures in health and disease. Nat. Commun. 10, 4706 (2019).
pubmed: 31624246
pmcid: 6797728
doi: 10.1038/s41467-019-12464-3
Stuart, T. et al. Comprehensive integration of single-cell data. Cell 177, 1888–1902 (2019).
pubmed: 31178118
pmcid: 6687398
doi: 10.1016/j.cell.2019.05.031
Tomiyama, H., Takata, H., Matsuda, T. & Takiguchi, M. Phenotypic classification of human CD8
pubmed: 15048710
doi: 10.1002/eji.200324478
van der Leun, A. M., Thommen, D. S. & Schumacher, T. N. CD8
pubmed: 32024970
pmcid: 7115982
doi: 10.1038/s41568-019-0235-4
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).
pubmed: 25765070
pmcid: 4993154
doi: 10.1126/science.aaa1348
Samstein, R. M. et al. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51, 202–206 (2019).
pubmed: 30643254
pmcid: 6365097
doi: 10.1038/s41588-018-0312-8
Anandappa, A. J., Wu, C. J. & Ott, P. A. Directing traffic: how to effectively drive T cells into tumors. Cancer Discov. 10, 185–197 (2020).
pubmed: 31974169
pmcid: 7007384
doi: 10.1158/2159-8290.CD-19-0790
Rojas, L. A. et al. Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer. Nature 618, 144–150 (2023).
pubmed: 37165196
pmcid: 10171177
doi: 10.1038/s41586-023-06063-y
Sayaman, R. W. et al. Germline genetic contribution to the immune landscape of cancer. Immunity 54, 367–386 (2021).
pubmed: 33567262
pmcid: 8414660
doi: 10.1016/j.immuni.2021.01.011
Finn, R. S. et al. Atezolizumab plus bevacizumab in unresectable hepatocellular carcinoma. N. Engl. J. Med. 382, 1894–1905 (2020).
pubmed: 32402160
doi: 10.1056/NEJMoa1915745
Qin, S. et al. Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study. Lancet 402, 1133–1146 (2023).
pubmed: 37499670
doi: 10.1016/S0140-6736(23)00961-3
Yau, T. et al. Efficacy and safety of nivolumab plus ipilimumab in patients with advanced hepatocellular carcinoma previously treated with sorafenib: the CheckMate 040 randomized clinical trial. JAMA Oncol. 6, e204564 (2020).
pubmed: 33001135
pmcid: 7530824
doi: 10.1001/jamaoncol.2020.4564
De Rosa, S. C. et al. Robust antibody and cellular responses induced by DNA-only vaccination for HIV. JCI Insight 5, e137079 (2020).
pubmed: 32437332
pmcid: 7406303
doi: 10.1172/jci.insight.137079
Janetzki, S. et al. Results and harmonization guidelines from two large-scale international Elispot proficiency panels conducted by the Cancer Vaccine Consortium (CVC/SVI). Cancer Immunol. Immunother. 57, 303–315 (2008).
pubmed: 17721781
doi: 10.1007/s00262-007-0380-6
Robins, H. S. et al. Comprehensive assessment of T-cell receptor β-chain diversity in αβ T cells. Blood 114, 4099–4107 (2009).
pubmed: 19706884
pmcid: 2774550
doi: 10.1182/blood-2009-04-217604
Robins, H. et al. Ultra-sensitive detection of rare T cell clones. J. Immunol. Methods 375, 14–19 (2012).
pubmed: 21945395
doi: 10.1016/j.jim.2011.09.001
Carlson, C. S. et al. Using synthetic templates to design an unbiased multiplex PCR assay. Nat. Commun. 4, 2680 (2013).
pubmed: 24157944
doi: 10.1038/ncomms3680
Hao, Y. et al. Integrated analysis of multimodal single-cell data. Cell 184, 3573–3587 (2021).
pubmed: 34062119
pmcid: 8238499
doi: 10.1016/j.cell.2021.04.048
Sundell, T. et al. Single-cell RNA sequencing analyses: interference by the genes that encode the B-cell and T-cell receptors. Brief. Funct. Genomics 22, 263–273 (2022).
pubmed: 36473726
pmcid: 10195088
doi: 10.1093/bfgp/elac044
Hafemeister, C. & Satija, R. Normalization and variance stabilization of single-cell RNA-seq data using regularized negative binomial regression. Genome Biol. 20, 296 (2019).
pubmed: 31870423
pmcid: 6927181
doi: 10.1186/s13059-019-1874-1
Ahlmann-Eltze, C. & Huber, W. glmGamPoi: fitting gamma–Poisson generalized linear models on single cell count data. Bioinformatics 36, 5701–5702 (2021).
pubmed: 33295604
doi: 10.1093/bioinformatics/btaa1009
Finak, G. et al. MAST: a flexible statistical framework for assessing transcriptional changes and characterizing heterogeneity in single-cell RNA sequencing data. Genome Biol. 16, 278 (2015).
pubmed: 26653891
pmcid: 4676162
doi: 10.1186/s13059-015-0844-5
Borcherding, N., Bormann, N. L. & Kraus, G. scRepertoire: an R-based toolkit for single-cell immune receptor analysis. F1000Res 9, 47 (2020).
pubmed: 32789006
pmcid: 7400693
doi: 10.12688/f1000research.22139.1
Payne, K. K. et al. BTN3A1 governs antitumor responses by coordinating αβ and γδ T cells. Science 369, 942–949 (2020).
pubmed: 32820120
pmcid: 7646930
doi: 10.1126/science.aay2767