Abstract
Within the past decade, the field of immunotherapy has revolutionized the treatment of many cancers with the development and regulatory approval of various immune-checkpoint inhibitors and chimeric antigen receptor T cell therapies in diverse indications. Another promising approach to cancer immunotherapy involves the use of personalized vaccines designed to trigger de novo T cell responses against neoantigens, which are highly specific to tumours of individual patients, in order to amplify and broaden the endogenous repertoire of tumour-specific T cells. Results from initial clinical studies of personalized neoantigen-based vaccines, enabled by the availability of rapid and cost-effective sequencing and bioinformatics technologies, have demonstrated robust tumour-specific immunogenicity and preliminary evidence of antitumour activity in patients with melanoma and other cancers. Herein, we provide an overview of the complex process that is necessary to generate a personalized neoantigen vaccine, review the types of vaccine-induced T cells that are found within tumours and outline strategies to enhance the T cell responses. In addition, we discuss the current status of clinical studies testing personalized neoantigen vaccines in patients with cancer and considerations for future clinical investigation of this novel, individualized approach to immunotherapy.
Key points
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Personalized therapeutic cancer vaccines predicated on neoantigens have been shown to be feasible, safe and immunogenic in patients with melanoma and glioblastoma.
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Different vaccine formats and delivery strategies are currently being tested in clinical studies involving patients with various tumour types.
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Deeper evaluation of the phenotypes, functionality and long-lasting memory potential of vaccine-induced neoantigen-specific CD4+ and CD8+ T cells is warranted to improve understanding of their therapeutic activity and optimize vaccination strategies.
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Neoantigen target discovery is continually being advanced to improve the identification of immunogenic neoepitopes that can be recognized by CD8+ T cells; algorithms for the more challenging task of predicting CD4+ T cell neoepitopes are also emerging.
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Innovative vaccine delivery platforms and the most effective timing of combinatorial therapies should be further explored to reduce costs and time delays and increase clinical efficacy.
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References
Hollingsworth, R. E. & Jansen, K. Turning the corner on therapeutic cancer vaccines. NPJ Vaccines 4, 7–10 (2019).
Vormehr, M., Türeci, Ö. & Sahin, U. Harnessing tumor mutations for truly individualized cancer vaccines. Annu. Rev. Med. 70, 395–407 (2019).
Alexandrov, L. B. et al. Signatures of mutational processes in human cancer. Nature 500, 415–421 (2013).
MD, S. T. et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18, 1009–1021 (2017).
Yang, W. et al. Immunogenic neoantigens derived from gene fusions stimulate T cell responses. Nat. Med. 25, 767–775 (2019).
Balachandran, V. P. et al. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 108, 914–934 (2017).
Martin, S. D. et al. Low mutation burden in ovarian cancer may limit the utility of neoantigen-targeted vaccines. PLoS ONE 11, e0155189 (2016).
Subudhi, S. K. et al. Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer. Sci. Transl Med. 12, eaaz3577 (2020).
Hilf, N. et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565, 240–245 (2019).
Keskin, D. B. et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565, 234–239 (2019).
van Rooij, N. et al. Tumor exome analysis reveals neoantigen-specific T-cell reactivity in an ipilimumab-responsive melanoma. J. Clin. Oncol. 31, e439–e442 (2013).
Tran, E. et al. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science 350, 1387–1390 (2015).
Giannakis, M. et al. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15, 857–865 (2016).
Brown, S. D. et al. Neo-antigens predicted by tumor genome meta-analysis correlate with increased patient survival. Genome Res. 24, 743–750 (2014).
Rooney, M. S., Shukla, S. A., Wu, C. J., Getz, G. & Hacohen, N. Molecular and genetic properties of tumors associated with local immune cytolytic activity. Cell 160, 48–61 (2015).
Strickland, K. C. et al. Association and prognostic significance of BRCA1/2-mutation status with neoantigen load, number of tumor-infiltrating lymphocytes and expression of PD-1/PD-L1 in high grade serous ovarian cancer. Oncotarget 7, 13587–13598 (2016).
Matsushita, H. et al. Neoantigen load, antigen presentation machinery, and immune signatures determine prognosis in clear cell renal cell carcinoma. Cancer Immunol. Res. 4, 463–471 (2016).
Snyder, A. et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N. Engl. J. Med. 371, 2189–2199 (2014).
Van Allen, E. M. et al. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350, 207–211 (2015).
McGranahan, N. et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science 351, 1463–1469 (2016).
Rizvi, N. A. et al. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348, 124–128 (2015).
Le, D. T. et al. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372, 2509–2520 (2015).
Chan, T. A. et al. Development of tumor mutation burden as an immunotherapy biomarker: utility for the oncology clinic. Ann. Oncol. 30, 44–56 (2019).
Keenan, T. E., Burke, K. P. & Van Allen, E. M. Genomic correlates of response to immune checkpoint blockade. Nat. Med. 25, 389–402 (2019).
Schumacher, T. N., Scheper, W. & Kvistborg, P. Cancer neoantigens. Annu. Rev. Immunol. 37, 173–200 (2019).
McDermott, D. F. et al. Clinical activity and molecular correlates of response to atezolizumab alone or in combination with bevacizumab versus sunitinib in renal cell carcinoma. Nat. Med. 24, 749–757 (2018).
Miao, D. et al. Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat. Genet. 50, 1271–1281 (2018).
Hugo, W. et al. Genomic and transcriptomic features of response to anti-PD-1 therapy in metastatic melanoma. Cell 165, 35–44 (2016).
Matsushita, H. et al. Cancer exome analysis reveals a T-cell-dependent mechanism of cancer immunoediting. Nature 482, 400–404 (2012).
Verdegaal, E. M. E. et al. Neoantigen landscape dynamics during human melanoma–T cell interactions. Nature 536, 91–95 (2016).
Anagnostou, V. et al. Evolution of neoantigen landscape during immune checkpoint blockade in non-small cell lung cancer. Cancer Discov. 7, 264–276 (2017).
Rosenthal, R. et al. Neoantigen-directed immune escape in lung cancer evolution. Nature 567, 479–485 (2019).
Zhao, J. et al. Immune and genomic correlates of response to anti-PD-1 immunotherapy in glioblastoma. Nat. Med. 25, 462–469 (2019).
Dagogo-Jack, I. & Shaw, A. T. Tumour heterogeneity and resistance to cancer therapies. Nat. Rev. Clin. Oncol. 15, 81–94 (2018).
Ott, P. A. et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547, 217–221 (2017).
Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547, 222–226 (2017).
Carreno, B. M. et al. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348, 803–808 (2015).
Hu, Z., Ott, P. A. & Wu, C. J. Towards personalized, tumour-specific, therapeutic vaccines for cancer. Nat. Rev. Immunol. 18, 168–182 (2018).
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).
Roudko, V., Greenbaum, B. & Bhardwaj, N. Computational prediction and validation of tumor-associated neoantigens. Front. Immunol. 11, 609–611 (2020).
Türeci, Ö. et al. Challenges towards the realization of individualized cancer vaccines. Nat. Biomed. Eng. 2, 566–569 (2018).
Robinson, J. et al. IPD-IMGT/HLA database. Nucleic Acids Res. 55, 280–288 (2019).
Fritsch, E. F. et al. HLA-binding properties of tumor neoepitopes in humans. Cancer Immunol. Res. 2, 522–529 (2014).
Peters, B., Nielsen, M. & Sette, A. T cell epitope predictions. Annu. Rev. Immunol. 38, 123–145 (2020).
Jurtz, V. et al. NetMHCpan-4.0: improved peptide-MHC class I interaction predictions integrating eluted ligand and peptide binding affinity data. J. Immunol. 199, 3360–3368 (2017).
Abelin, J. G. et al. Mass spectrometry profiling of HLA-associated peptidomes in mono-allelic cells enables more accurate epitope prediction. Immunity 46, 315–326 (2017).
Bulik-Sullivan, B. et al. Deep learning using tumor HLA peptide mass spectrometry datasets improves neoantigen identification. Nat. Biotechnol. 37, 55–63 (2019).
Sarkizova, S. et al. A large peptidome dataset improves HLA class I epitope prediction across most of the human population. Nat. Biotechnol. 38, 199–209 (2020).
Capietto, A.-H. et al. Mutation position is an important determinant for predicting cancer neoantigens. J. Exp. Med. 217, 315–322 (2020).
Andreatta, M. et al. Accurate pan-specific prediction of peptide-MHC class II binding affinity with improved binding core identification. Immunogenetics 67, 641–650 (2015).
Bijker, M. S. et al. CD8+ CTL priming by exact peptide epitopes in incomplete freund’s adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity. J. Immunol. 179, 5033–5040 (2007).
Kenter, G. G. et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N. Engl. J. Med. 361, 1838–1847 (2009).
Kreiter, S. et al. Mutant MHC class II epitopes drive therapeutic immune responses to cancer. Nature 520, 692–696 (2015).
Rossjohn, J. et al. T cell antigen receptor recognition of antigen-presenting molecules. Annu. Rev. Immunol. 33, 169–200 (2015).
Mildner, A. & Jung, S. Development and function of dendritic cell subsets. Immunity 40, 642–656 (2014).
Abelin, J. G. et al. Defining HLA-II ligand processing and binding rules with mass spectrometry enhances cancer epitope prediction. Immunity 51, 766–779.e17 (2019).
Racle, J. et al. Robust prediction of HLA class II epitopes by deep motif deconvolution of immunopeptidomes. Nat. Biotechnol. 37, 1283–1286 (2019).
Reynisson, B. et al. Improved prediction of MHC II antigen presentation through integration and motif deconvolution of mass spectrometry MHC eluted ligand data. J. Proteome Res. 19, 2304–2315 (2020).
Harari, A., Graciotti, M., Bassani-Sternberg, M. & Kandalaft, L. E. Antitumour dendritic cell vaccination in a priming and boosting approach. Nat. Rev. Drug Discov. 19, 635–652 (2020).
Tanyi, J. L. et al. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer. Sci. Transl Med. 10, eaao5931 (2018).
Lu, Y.-C. et al. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin. Cancer Res. 20, 3401–3410 (2014).
Lu, Y.-C. et al. An efficient single-cell RNA-Seq approach to identify neoantigen-specific T cell receptors. Mol. Ther. 26, 379–389 (2018).
Cafri, G. et al. Memory T cells targeting oncogenic mutations detected in peripheral blood of epithelial cancer patients. Nat. Commun. 10, 449 (2019).
Leko, V. et al. Identification of neoantigen-reactive tumor-infiltrating lymphocytes in primary bladder cancer. J. Immunol. 202, 3458–3467 (2019).
Lawrence, M. S. et al. Mutational heterogeneity in cancer and the search for new cancer-associated genes. Nature 499, 214–218 (2013).
Malonis, R. J., Lai, J. R. & Vergnolle, O. Peptide-based vaccines: current progress and future challenges. Chem. Rev. 120, 3210–3229 (2020).
Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Clin. Oncol. 17, 261–279 (2018).
Gary, E. N. & Weiner, D. B. DNA vaccines: prime time is now. Curr. Opin. Immunol. 65, 21–27 (2020).
Saxena, M. & Bhardwaj, N. Re-emergence of dendritic cell vaccines for cancer treatment. Trends Cancer 4, 119–137 (2018).
Humphreys, I. R. & Sebastian, S. Novel viral vectors in infectious diseases. Immunology 153, 1–9 (2017).
Harty, J. T. & Badovinac, V. P. Shaping and reshaping CD8+ T-cell memory. Nat. Rev. Immunol. 8, 107–119 (2008).
Fraser, K. A., Schenkel, J. M., Jameson, S. C., Vezys, V. & Masopust, D. Preexisting high frequencies of memory CD8+ T cells favor rapid memory differentiation and preservation of proliferative potential upon boosting. Immunity 39, 171–183 (2013).
Wirth, T. C. et al. Repetitive antigen stimulation induces stepwise transcriptome diversification but preserves a core signature of memory CD8+ T cell differentiation. Immunity 33, 128–140 (2010).
Masopust, D., Ha, S.-J., Vezys, V. & Ahmed, R. Stimulation history dictates memory CD8 T cell phenotype: implications for prime-boost vaccination. J. Immunol. 177, 831–839 (2006).
Sallusto, F., Lanzavecchia, A., Araki, K. & Ahmed, R. From vaccines to memory and back. Immunity 33, 451–463 (2010).
Tscharke, D. C., Croft, N. P., Doherty, P. C. & La Gruta, N. L. Sizing up the key determinants of the CD8 + T cell response. Nat. Rev. Immunol. 15, 705–716 (2015).
Kaech, S. M. & Cui, W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat. Rev. Immunol. 12, 749–761 (2012).
Martin, M. D. & Badovinac, V. P. Defining memory CD8 T cell. Front. Immunol. 9, 2692 (2018).
Plitas, G. & Rudensky, A. Y. Regulatory T cells in cancer. Annu. Rev. Cancer Biol. 4, 459–477 (2020).
Wculek, S. K. et al. Dendritic cells in cancer immunology and immunotherapy. Nat. Rev. Immunol. 20, 7–24 (2019).
Jameson, S. C. & Masopust, D. Understanding subset diversity in T cell memory. Immunity 48, 214–226 (2018).
Gerlach, C. et al. The chemokine receptor CX3CR1 defines three antigen-experienced CD8 T cell subsets with distinct roles in immune surveillance and homeostasis. Immunity 45, 1270–1284 (2016).
Schenkel, J. M. et al. Resident memory CD8 T cells trigger protective innate and adaptive immune responses. Science 346, 98–101 (2014).
Mueller, S. N. & Mackay, L. K. Tissue-resident memory T cells: local specialists in immune defence. Nat. Rev. Immunol. 16, 79–89 (2015).
Szabo, P. A., Miron, M. & Farber, D. L. Location, location, location: tissue resident memory T cells in mice and humans. Sci. Immunol. 4, eaas9673 (2019).
Gebhardt, T. et al. Different patterns of peripheral migration by memory CD4+ and CD8+ T cells. Nature 477, 216–219 (2011).
Park, S. L., Gebhardt, T. & Mackay, L. K. Tissue-resident memory T cells in cancer immunosurveillance. Trends Immunol. 40, 735–747 (2019).
Blanc, C. et al. Targeting resident memory T cells for cancer immunotherapy. Front. Immunol. 9, 524–527 (2018).
Nizard, M. et al. Induction of resident memory T cells enhances the efficacy of cancer vaccine. Nat. Commun. 8, 1–11 (2017).
Ganesan, A.-P. et al. Tissue-resident memory features are linked to the magnitude of cytotoxic T cell responses in human lung cancer. Nat. Immunol. 18, 940–950 (2017).
Duhen, T. et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat. Commun. 9, 2724 (2018).
Clarke, J. et al. Single-cell transcriptomic analysis of tissue-resident memory T cells in human lung cancer. J. Exp. Med. 216, 2128–2149 (2019).
Dijkgraaf, F. E. et al. Tissue patrol by resident memory CD8+ T cells in human skin. Nat. Immunol. 20, 756–764 (2019).
Steinert, E. M. et al. Quantifying memory CD8 T cells reveals regionalization of immunosurveillance. Cell 161, 737–749 (2015).
McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).
Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).
Angelosanto, J. M., Blackburn, S. D., Crawford, A. & Wherry, E. J. Progressive loss of memory T cell potential and commitment to exhaustion during chronic viral infection. J. Virol. 86, 8161–8170 (2012).
Pauken, K. E. et al. Epigenetic stability of exhausted T cells limits durability of reinvigoration by PD-1 blockade. Science 354, 1160–1165 (2016).
Philip, M. et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452–456 (2017).
Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).
Ghoneim, H. E. et al. De novo epigenetic programs inhibit PD-1 blockade- mediated T cell rejuvenation. Cell 170, 142–157.e19 (2017).
Scott-Browne, J. P. et al. Dynamic changes in chromatin accessibility occur in CD8. Immunity 45, 1327–1340 (2016).
Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 476, 465–470 (2019).
Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019).
Brummelman, J. et al. High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors. J. Exp. Med. 215, 2520–2535 (2018).
Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211.e10 (2019).
Laidlaw, B. J., Craft, J. E. & Kaech, S. M. The multifaceted role of CD4+T cells in CD8+T cell memory. Nat. Rev. Immunol. 16, 102–111 (2016).
Baxevanis, C. N. et al. Tumor-specific CD4+T lymphocytes from cancer patients are required for optimal induction of cytotoxic T cells against the autologous tumor. J. Immunol. 164, 3902–3912 (2000).
Marzo, A. L. et al. Tumor-specific CD4+ T cells have a major ‘post-licensing’ role in CTL mediated anti-tumor immunity. J. Immunol. 165, 6047–6055 (2000).
Ossendorp, F., Mengedé, E., Camps, M., Filius, R. & Melief, C. J. Specific T helper cell requirement for optimal induction of cytotoxic T lymphocytes against major histocompatibility complex class II negative tumors. J. Exp. Med. 187, 693–702 (1998).
Alspach, E. et al. MHC-II neoantigens shape tumour immunity and response to immunotherapy. Nature 574, 696–701 (2019).
Zander, R. et al. CD4+ T cell help is required for the formation of a cytolytic CD8+T cell subset that protects against chronic infection and cancer. Immunity 51, 1028–1042.e4 (2019).
Ahrends, T. & Borst, J. The opposing roles of CD4+ T cells in anti-tumour immunity. Immunology 154, 582–592 (2018).
Bos, R. & Sherman, L. A. CD4+ T-cell help in the tumor milieu is required for recruitment and cytolytic function of CD8+ T lymphocytes. Cancer Res. 70, 8368–8377 (2010).
Corthay, A. et al. Primary antitumor immune response mediated by CD4+ T cells. Immunity 22, 371–383 (2005).
Wong, S. B. J., Bos, R. & Sherman, L. A. Tumor-specific CD4+ T cells render the tumor environment permissive for infiltration by low-avidity CD8+ T cells. J. Immunol. 180, 3122–3131 (2008).
Mumberg, D. et al. CD4+ T cells eliminate MHC class II-negative cancer cells in vivo by indirect effects of IFN-gamma. Proc. Natl Acad. Sci. USA 96, 8633–8638 (1999).
Spitzer, M. H. et al. Systemic immunity is required for effective cancer immunotherapy. Cell 168, 487–502.e15 (2017).
Linnemann, C. et al. High-throughput epitope discovery reveals frequent recognition of neo-antigens by CD4+ T cells in human melanoma. Nat. Med. 21, 81–85 (2014).
Hunder, N. N. et al. Treatment of metastatic melanoma with autologous CD4+T cells against NY-ESO-1. N. Engl. J. Med. 358, 2698–2703 (2008).
Tran, E. et al. Cancer immunotherapy based on mutation-specific CD4+T cells in a patient with epithelial cancer. Science 344, 641–645 (2014).
Melssen, M. & Slingluff, C. L. Jr. Vaccines targeting helper T cells for cancer immunotherapy. Curr. Opin. Immunol. 47, 85–92 (2017).
Wilk, M. M. & Mills, K. H. G. CD4 TRM cells following infection and immunization: implications for more effective vaccine design. Front. Immunol. 9, 2413–2418 (2018).
Aarntzen, E. H. J. G. et al. Targeting CD4+T-helper cells improves the induction of antitumor responses in dendritic cell–based vaccination. Cancer Res. 73, 19–29 (2013).
Ahrends, T. et al. CD4+T cell help confers a cytotoxic T cell effector program including coinhibitory receptor downregulation and increased tissue invasiveness. Immunity 47, 848–861.e5 (2017).
Moynihan, K. D. et al. Eradication of large established tumors in mice by combination immunotherapy that engages innate and adaptive immune responses. Nat. Med. 22, 1402–1410 (2016).
Jaigirdar, S. A. & MacLeod, M. K. L. Development and function of protective and pathologic memory CD4 T cells. Front. Immunol. 6, 456 (2015).
Magen, A. et al. Single-cell profiling defines transcriptomic signatures specific to tumor-reactive versus virus-responsive CD4+T cells. Cell Rep. 29, 3019–3032.e6 (2019).
Axelrod, M. L., Cook, R. S., Johnson, D. B. & Balko, J. M. Biological consequences of MHC-II expression by tumor cells in cancer. Clin. Cancer Res. 25, 2392–2402 (2019).
Quezada, S. A. et al. Tumor-reactive CD4+T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. J. Exp. Med. 207, 637–650 (2010).
Oh, D. Y. et al. Intratumoral CD4+ T cells mediate anti-tumor cytotoxicity in human bladder cancer. Cell 181, 1612–1625 (2020).
Ahmadzadeh, M. et al. Tumor-infiltrating human CD4+ regulatory T cells display a distinct TCR repertoire and exhibit tumor and neoantigen reactivity. Sci. Immunol. 4, eaao4310 (2019).
Cohen, R. B. et al. GEN-009, a neoantigen vaccine containing ATLAS selected neoantigens, to generate broad sustained immunity against immunogenic tumor mutations and avoid inhibitory peptides. J. Clin. Oncol. 38, 3107–3107 (2020).
Nogueira, C., Kaufmann, J. K., Lam, H. & Flechtner, J. B. Improving cancer immunotherapies through empirical neoantigen selection. Trends Cancer 4, 97–100 (2018).
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, bladder cancer. Cell 183, 347–362.e24 (2020).
Cohen, R. B. et al. Broad immunogenicity from GEN-009, a neoantigen vaccine using ATLASTM, an autologous immune assay, to identify immunogenic and inhibitory tumor neoantigens. J. Immunother. Cancer 7 (Suppl. 1), P420 (2019).
Lopez, J. S. et al. A phase Ib study to evaluate RO7198457, an individualized neoantigen specific immunotherapy (iNeST), in combination with atezolizumab in patients with locally advanced or metastatic solid tumors. Cancer Res. 80, CT301 (2020).
Burris, H. A. et al. A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. J. Clin. Oncol. 37 (Suppl. 15), 2523 (2019).
Hammerich, L. et al. Systemic clinical tumor regressions and potentiation of PD1 blockade with in situ vaccination. Nat. Med. 25, 814–824 (2019).
Sahin, U. & Türeci, Ö. Personalized vaccines for cancer immunotherapy. Science 359, 1355–1360 (2018).
Verma, V. et al. PD-1 blockade in subprimed CD8 cells induces dysfunctional PD-1+ CD38hi cells and anti-PD-1 resistance. Nat. Immunol. 20, 1231–1243 (2019).
Rajasagi, M. et al. Systematic identification of personal tumor-specific neoantigens in chronic lymphocytic leukemia. Blood 124, 453–462 (2014).
Blazquez, A. et al. A phase I study of the safety and immunogenicity of a multi-peptide personalized genomic vaccine in the adjuvant treatment of solid tumors and hematological malignancies. J. Clin. Oncol. 37 (Suppl. 15), e14307 (2019).
Rubinsteyn, A. et al. Computational pipeline for the PGV-001 neoantigen vaccine trial. Front. Immunol. 8, 1807 (2017).
Wesolowski R. et al. A phase 1 study of safety and tolerability of AutoSynVax™ vaccine in patients with advanced cancer. Presented at the Society for the Immunotherapy of Cancer Annual Meeting (2018).
Krauss J. et al. Preliminary safety, efficacy and immunogenicity results from a phase 1/2a study (DIRECT-01) of cancer neoantigen DNA vaccine VB10.NEO in patients with locally advanced or metastatic solid tumors. Presented at the Society for the Immunotherapy of Cancer Annual Meeting (2019).
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The work of P.A.O. is supported by the National Institute for Health Research (NIHR) Efficacy and Mechanism Evaluation Programme (National Cancer Institute grant 1R01CA229261-01), a Team Science Award from the Melanoma Research Alliance, the Francis and Adele Kittredge Family Immuno-Oncology and Melanoma Research Fund, the Faircloth Family Research Fund, the Bender Family Research Fund, and the Dana-Farber Cancer Institute (DFCI) Center for Cancer Immunotherapy Research fellowship.
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P.A.O. has received research funding from and has been an adviser of Amgen, Armo BioSciences, Array, AstraZeneca/MedImmune, Bristol-Myers Squibb, Celldex, CytomX, Merck, Neon Therapeutics, Novartis, Pfizer and Roche/Genentech. E.B. declares no competing interests.
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Blass, E., Ott, P.A. Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. Nat Rev Clin Oncol 18, 215–229 (2021). https://doi.org/10.1038/s41571-020-00460-2
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DOI: https://doi.org/10.1038/s41571-020-00460-2
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