Individualized, heterologous chimpanzee adenovirus and self-amplifying mRNA neoantigen vaccine 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:
08 2022
08 2022
Historique:
received:
04
03
2022
accepted:
06
07
2022
pubmed:
16
8
2022
medline:
23
8
2022
entrez:
15
8
2022
Statut:
ppublish
Résumé
Checkpoint inhibitor (CPI) therapies provide limited benefit to patients with tumors of low immune reactivity. T cell-inducing vaccines hold promise to exert long-lasting disease control in combination with CPI therapy. Safety, tolerability and recommended phase 2 dose (RP2D) of an individualized, heterologous chimpanzee adenovirus (ChAd68) and self-amplifying mRNA (samRNA)-based neoantigen vaccine in combination with nivolumab and ipilimumab were assessed as primary endpoints in an ongoing phase 1/2 study in patients with advanced metastatic solid tumors (NCT03639714). The individualized vaccine regimen was safe and well tolerated, with no dose-limiting toxicities. Treatment-related adverse events (TRAEs) >10% included pyrexia, fatigue, musculoskeletal and injection site pain and diarrhea. Serious TRAEs included one count each of pyrexia, duodenitis, increased transaminases and hyperthyroidism. The RP2D was 10
Identifiants
pubmed: 35970920
doi: 10.1038/s41591-022-01937-6
pii: 10.1038/s41591-022-01937-6
doi:
Substances chimiques
RNA, Messenger
0
Banques de données
ClinicalTrials.gov
['NCT03639714']
Types de publication
Clinical Trial, Phase I
Clinical Trial, Phase II
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1619-1629Informations de copyright
© 2022. The Author(s), under exclusive licence to Springer Nature America, Inc.
Références
Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).
pubmed: 23770567
pmcid: 3919509
doi: 10.1038/nature12213
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
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
pubmed: 25409260
pmcid: 4315319
doi: 10.1056/NEJMoa1406498
Lee, C. H., Yelensky, R., Jooss, K. & Chan, T. A. Update on tumor neoantigens and their utility: why it is good to be different. Trends Immunol. 39, 536–548 (2018).
pubmed: 29751996
pmcid: 7954132
doi: 10.1016/j.it.2018.04.005
Tran, E., Robbins, P. F. & Rosenberg, S. A. ‘Final common pathway’ of human cancer immunotherapy: targeting random somatic mutations. Nat. Immunol. 18, 255–262 (2017).
pubmed: 28198830
pmcid: 6295671
doi: 10.1038/ni.3682
DuPage, M., Mazumdar, C., Schmidt, L. M., Cheung, A. F. & Jacks, T. Expression of tumour-specific antigens underlies cancer immunoediting. Nature 482, 405–409 (2012).
pubmed: 22318517
pmcid: 3288744
doi: 10.1038/nature10803
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
Lennerz, V. et al. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc. Natl Acad. Sci. USA 102, 16013–16018 (2005).
pubmed: 16247014
pmcid: 1266037
doi: 10.1073/pnas.0500090102
Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).
pubmed: 22318521
pmcid: 3874809
doi: 10.1038/nature10755
Robbins, P. F. et al. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19, 747–752 (2013).
pubmed: 23644516
pmcid: 3757932
doi: 10.1038/nm.3161
Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).
pubmed: 25428505
pmcid: 4246418
doi: 10.1038/nature13954
McGranahan, N. & Swanton, C. Neoantigen quality, not quantity. Sci. Transl. Med. 11, eaax7918 (2019).
pubmed: 31434757
doi: 10.1126/scitranslmed.aax7918
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
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
Ott, P. A. et al. A phase Ib trial of personalized neoantigen therapy plus anti-PD-1 in patients with advanced melanoma, non-small cell lung cancer, or bladder cancer. Cell 183, 347–362.e324 (2020).
pubmed: 33064988
doi: 10.1016/j.cell.2020.08.053
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
Sahin, U. et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature 585, 107–112 (2020).
pubmed: 32728218
doi: 10.1038/s41586-020-2537-9
Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565, 240–245 (2019).
pubmed: 30568303
doi: 10.1038/s41586-018-0810-y
Riaz, N. et al. Tumor and microenvironment evolution during immunotherapy with nivolumab. Cell 171, 934–949 e916 (2017).
pubmed: 29033130
pmcid: 5685550
doi: 10.1016/j.cell.2017.09.028
Shaw, A. R. & Suzuki, M. Immunology of adenoviral vectors in cancer therapy. Mol. Ther. Methods Clin. Dev. 15, 418–429 (2019).
pubmed: 31890734
pmcid: 6909129
doi: 10.1016/j.omtm.2019.11.001
Lopez-Camacho, C. et al. Rational Zika vaccine design via the modulation of antigen membrane anchors in chimpanzee adenoviral vectors. Nat. Commun. 9, 2441 (2018).
pubmed: 29934593
pmcid: 6015009
doi: 10.1038/s41467-018-04859-5
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, 286re285 (2015).
doi: 10.1126/scitranslmed.aaa2373
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).
pubmed: 32702298
pmcid: 7445431
doi: 10.1016/S0140-6736(20)31604-4
& Sadoff, J. et al. Interim results of a phase 1-2a trial of Ad26.COV2.S covid-19 vaccine.N. Engl. J. Med. 384, 1824–1835 (2021).
pubmed: 33440088
doi: 10.1056/NEJMoa2034201
Zhao, H. et al. Seroprevalence of neutralizing antibodies against human adenovirus type-5 and chimpanzee adenovirus type-68 in cancer patients. Front Immunol. 9, 335 (2018).
pubmed: 29563911
pmcid: 5845880
doi: 10.3389/fimmu.2018.00335
Lundstrom, K. RNA viruses as tools in gene therapy and vaccine development. Genes (Basel) 10, 189 (2019).
doi: 10.3390/genes10030189
Mulligan, M. J. et al. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 586, 589–593 (2020).
pubmed: 32785213
doi: 10.1038/s41586-020-2639-4
McNamara, M. A., Nair, S. K. & Holl, E. K. RNA-based vaccines in cancer immunotherapy. J. Immunol. Res 2015, 794528 (2015).
pubmed: 26665011
pmcid: 4668311
doi: 10.1155/2015/794528
Allen, T. M. et al. CD8+ Lymphocytes from simian immunodeficiency virus-infected rhesus macaques recognize 14 different epitopes bound by the major histocompatibility complex class i molecule Mamu-A*01: implications for vaccine design and testing. J. Virol. 75, 738–749 (2001).
pubmed: 11134287
pmcid: 113970
doi: 10.1128/JVI.75.2.738-749.2001
Bulik-Sullivan, B. et al. Deep learning using tumor HLA peptide mass spectrometry datasets improves neoantigen identification. Nat. Biotechnol., https://doi.org/10.1038/nbt.4313 (2018).
Chen, E. X. et al. Effect of combined immune checkpoint inhibition vs best supportive care alone in patients with advanced colorectal cancer: the Canadian Cancer Trials Group CO.26 Study. JAMA Oncol. 6, 831–838 (2020).
pubmed: 32379280
doi: 10.1001/jamaoncol.2020.0910
Bendell, J. et al. Efficacy and safety results from IMblaze370, a randomised phase III study comparing atezolizumab1cobimetinib and atezolizumab monotherapy vs regorafenib in chemotherapy-refractory metastatic colorectal cancer. Ann. Oncol. 29, v123 (2018). 2018.
doi: 10.1093/annonc/mdy208.003
Grothey, A. et al. Fluoropyrimidine (FP) 1 bevacizumab (BEV) 1 atezolizumab vs FP/BEV in BRAFwt metastatic colorectal cancer (mCRC): findings from cohort 2 of MODUL–a multicentre, randomized trial of biomarkerdriven maintenance treatment following first-line induction therapy. Ann. Oncol. 29, viii714–viii715 (2018).
doi: 10.1093/annonc/mdy424.020
Farber, D. L., Yudanin, N. A. & Restifo, N. P. Human memory T cells: generation, compartmentalization and homeostasis. Nat. Rev. Immunol. 14, 24–35 (2014).
pubmed: 24336101
doi: 10.1038/nri3567
Trolle, T. et al. The length distribution of class I-restricted T cell epitopes is determined by both peptide supply and MHC allele-specific binding preference. J. Immunol. 196, 1480–1487 (2016).
pubmed: 26783342
doi: 10.4049/jimmunol.1501721
Wieczorek, M. et al. Major histocompatibility complex (MHC) class I and MHC class II proteins: conformational plasticity in antigen presentation. Front Immunol. 8, 292 (2017).
pubmed: 28367149
pmcid: 5355494
doi: 10.3389/fimmu.2017.00292
Chudley, L. et al. Harmonisation of short-term in vitro culture for the expansion of antigen-specific CD8
pubmed: 25134947
pmcid: 4209099
doi: 10.1007/s00262-014-1593-0
Zhang, Q. et al. Prognostic and predictive impact of circulating tumor DNA in patients with advanced cancers treated with immune checkpoint blockade. Cancer Disco. 10, 1842–1853 (2020).
doi: 10.1158/2159-8290.CD-20-0047
McGranahan, N. et al. Allele-specific HLA loss and immune escape in lung cancer evolution. Cell 171, 1259–1271 (2017).
pubmed: 29107330
pmcid: 5720478
doi: 10.1016/j.cell.2017.10.001
Rosenthal, R. et al. Neoantigen-directed immune escape in lung cancer evolution. Nature 567, 479–485 (2019).
pubmed: 30894752
pmcid: 6954100
doi: 10.1038/s41586-019-1032-7
Paulson, K. G. et al. Acquired cancer resistance to combination immunotherapy from transcriptional loss of class I HLA. Nat. Commun. 9, 3868 (2018).
pubmed: 30250229
pmcid: 6155241
doi: 10.1038/s41467-018-06300-3
Piperno-Neumann, S. et al. Phase 3 randomized trial comparing tebentafusp with investigator’s choice in first line metastatic uveal melanoma.Cancer Res. 18, CT002 (2021).
doi: 10.1158/1538-7445.AM2021-CT002
Rappaport, A. R. et al. Low-dose self-amplifying mRNA COVID-19 vaccine drives strong protective immunity in non-human primates against SARS-CoV-2 infection. Nat. Commun. 13, 3289 (2022).
pubmed: 35672369
pmcid: 9173840
doi: 10.1038/s41467-022-31005-z
Moodie, Z. et al. Response definition criteria for ELISPOT assays revisited. Cancer Immunol. Immunother. 59, 1489–1501 (2010).
pubmed: 20549207
pmcid: 2909425
doi: 10.1007/s00262-010-0875-4
Janetzki, S. et al. Guidelines for the automated evaluation of Elispot assays. Nat. Protoc. 10, 1098–1115 (2015).
pubmed: 26110715
doi: 10.1038/nprot.2015.068
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).
pubmed: 23569307
pmcid: 3641699
doi: 10.1200/JCO.2012.45.7903
Janetzki, S., Cox, J. H., Oden, N. & Ferrari, G. Standardization and validation issues of the ELISPOT assay. Methods Mol. Biol. 302, 51–86 (2005).
pubmed: 15937345
Roederer, M., Nozzi, J. L. & Nason, M. C. SPICE: exploration and analysis of post-cytometric complex multivariate datasets. Cytom. A 79, 167–174 (2011).
doi: 10.1002/cyto.a.21015
Love, M. I., Huber, W. & Anders, S. Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol. 15, 550 (2014).
pubmed: 25516281
pmcid: 4302049
doi: 10.1186/s13059-014-0550-8
Ayers, M. et al. IFN-γ-related mRNA profile predicts clinical response to PD-1 blockade. J. Clin. Invest. 127, 2930–2940 (2017).
pubmed: 28650338
pmcid: 5531419
doi: 10.1172/JCI91190
Chalmers, Z. R. et al. Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden. Genome Med 9, 34 (2017).
pubmed: 28420421
pmcid: 5395719
doi: 10.1186/s13073-017-0424-2