Table Info

Table 2.

Clinical trials with TAA and neoantigens-based cancer vaccines encoding

Organ	Cancer type/stage	Phases	Cancer vaccine	TAA/neoantigens	Formulation	Study results	Sponsor	NCT number	Reference
Lung	NSCLC Stage IIIB or IV	Phase IIB trial	TG4010	MUC1	TG4010: recombinant modified vaccinia virus strain Ankara (MVA) encoding MUC1 and human interleukin 2 (IL-2)	TG4010 enhances the effect of chemotherapy in advanced NSCLC patients	Transgene SA (France)	NCT00415818	[50]
Lung	NSCLC Stage IIIA vs. IIIB	START study: phase III trial	Stimuvax	MUC1	Tecemotide: MUC1-derived 25-amino acid BLP25 lipopeptide, immunoadjuvant monophosphoryl lipid A, and three liposome-forming lipids	No significant difference in overall survival for all patients	Merck KgaA (Germany)	NCT00409188	[49]
Lung	NSCLC Stage IB, II and IIIA	Phase III trial	MAGE-A3 (AS15 and AS02B)	MAGE-A3	Adjuvant treatment with MAGE-A3	MAGE-A3 immunotherapeutic use in NSCLC has been stopped	GlaxoSmithKline (GSK) Biologicals SA (UK)	NCT00480025	[47]
Lung	NSCLC Stage IB to IIIA	Phase I dose escalation	PRAME (with AS15)	PRAME	PRAME recombinant protein with AS15	Anti-PRAME humoral responses with no cancer regression stopped due to negative results	GSK Biologicals SA (UK)	NCT01159964	[48]
Lung	NSCLC Stage IIIB/IV	Phase II trial	Personalized peptide vaccine with docetaxel	Several TAA	31 Peptides from several TAA	Positive predictive value (PPV) may be efficacious for the humoral immunological responders but did not improve survival in combination with docetaxel for NSCLC patients	Kurume University Research Center for Innovative Cancer Therapy Kurume University School of Medicine (Japan)	UMIN Clinical Trials Registry (UMIN number 000003521)	[53]
Skin	Melanoma Stage IIIA-C/IV	Phase I trial	IVAC mutanome	Multiple neoantigens	Poly-neo-epitopic coding RNA vaccine	Immune responses to the majority of neoantigens contained in the vaccine/vaccine-induced T-cell responses in all vaccinated melanoma patients	BioNTech RNA Pharmaceuticals GmbH (Germany)	NCT02035956	[37]
Lung	NSCLC Stage IV	TIME study: phase IIB/III trial	TG4010	MUC1	TG4010: recombinant MVA encoding MUC1 and human IL-2	TG4010 modulates CD8⁺ T-cell response with improvements in clinical outcome	Not applicable	NCT01383148	[52]
Brain	Glioblastoma Stage IV	Phase I trial	Actively personalized vaccine 1 (APVAC1)	7 Non-mutated peptides, 1 viral peptide, and 2 tumor-associated peptides	APVAC1 vaccine plus poly-ICLC (Hiltonol^®) and GM-CSF	Unmutated APVAC1 antigens elicited sustained responses of central memory CD8⁺ T cells	Immatics Biotechnologies GmbH (Germany)	NCT02149225	[56]
Brain	Glioblastoma Stage IV	Phase I trial	Glioblastoma personalized peptide vaccine (GBM PVax)	8 Synthetic long peptides targeting seven neoantigens	Personalized neoantigen-based long peptide vaccine with poly-ICLC (Hiltonol^®)	Specific T-cell responses in the blood	Washington University School of Medicine (USA)	NCT02510950	[57]
Brain	Glioblastoma Stage IV	Phase I/IB trial	Personalized neoantigen targeting vaccine	20 Long peptides divided into pools of 3–5 peptides admixed with poly-ICLC	Neoantigen vaccine with radiation therapy plus pembrolizumab	Polyfunctional neoantigen-specific CD4⁺ and CD8⁺ T-cell responses exhibiting memory phenotype	Dana-Farber Cancer Institute (USA)	NCT02287428	[58]
Lung	NSCLC Stage IV	Phase II trial	Tedopi^®	5 TAA (CEA, p53, HER2/neu, MAGE2 and MAGE3)	Tedopi plus docetaxel or tedopi plus nivolumab	T-cell response with a better survival rate	OSE Immunotherapeutics (France)	NCT04884282	[54]
Digestive system	Gastrointestinal Stage IV	Phase I/II trial	mRNA-4650	Up to 20 different neoantigens	Neoantigen mRNA-based cancer vaccine	mRNA-4650 vaccine was safe and elicited mutation-specific T-cell responses against predicted neoepitopes	National Cancer Institute (USA)	NCT03480152	[59]
Skin	Melanoma Stage IIIB, C, and IV	Phase I (Lipo-MERIT trial)	FixVac (BNT 111)	4 TAA (NY-ESO-1, MAGE-A3, tyrosinase, and TPTE)	Liposomal RNA (RNA-LPX) vaccine	Strong CD4⁺ and CD8⁺ T-cell immunity against the vaccine antigens/antigen-specific cytotoxic T-cell responses in some responders reach magnitudes and are durable	BioNTech SE (Germany)	NCT02410733	[40]
Lung	Advanced lung cancer Stage IV	Phase I trial	Neo-DCVac	13–30 Peptide-based neoantigens	Neoantigen-pulsed DC vaccine	Neo-DCVac was well tolerated, safe, and capable of eliciting specific T-cell immunity and therapeutic benefit	Sichuan University (China)	NCT02956551 and Chinese Clinical Trial Registry (ChiCTRONC-16009100)	[60]
Skin	Melanoma Stage IIIB/C and IVM1a/b	Phase I trial	NeoVax	Long-peptide vaccine targeting up to 20 personal neoantigens	Neoantigen vaccine with poly-ICLC (Hiltonol^®)	T-cell responses with ex vivo detection of neoantigen-specific T cells exhibiting memory phenotype	Patrick Ott, MD (USA)	NCT01970358	[61]
Brain	Glioma Stage III/IV	Phase I trial	Isocitrate dehydrogenase type 1 (IDH1)-vac	20-Mer peptide-based neoantigens encompassing IDH1R132H-mutated region	IDH1 peptide vaccine with Montanide^®	IDH1 was immunogenic and induces specific T helper cell responses	National Center for Tumor Diseases (Germany)	NCT02454634	[62]
Pancreas	Pancreatic carcinoma Stage IV	Phase I trial	iNeo-Vac-P01	5–20 Peptides-based neoantigens	Neoantigen-based peptide vaccine (iNeo-Vac-P01) with adjuvant (GM-CSF)	No severe vaccine-related adverse effects/higher peripheral IFN-γ titer and CD4⁺ or CD8⁺ effector memory T cells count post-vaccination	Zhejiang Provincial People’s Hospital (China)	NCT03645148	[63]

GM-CSF: granulocyte-macrophage colony-stimulating factor; IFN-γ: interferon-γ

Declarations

Acknowledgments

The authors thank Sarah MacKenzie for editorial help.

Author contributions

MOA, SC and FMC: Conceptualization. MOA and SC: Creation of tables and figures. All authors contributed to the manuscript revision, read and approved the submitted version.

Conflicts of interest

The authors declare that they have no conflicts of interest.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publication

Not applicable.

Availability of data and materials

Not applicable.

Funding

This work was supported by grants from the French Institut National du Cancer (INCa; Grant number PRTK-2020-070); Agence Nationale de la Recherche (ANR-PRCE-2021, ANR-21-CE17-0049-01) and Fondation de France (2021; Grant number 00119144/WB-2021-34171). SC is supported by grants from Association pour la Recherche sur le Cancer (ARC; Grant number SIGN’IT20181007792). MOA is a recipient of a fellowship from Fondation de France (2021; Grant number 00119144/WB-2021-34171). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Copyright

References

Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480–9. [DOI] [PubMed] [PMC]

Sharma P, Allison JP. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell. 2015;161:205–14. [DOI] [PubMed] [PMC]

Hinrichs CS, Rosenberg SA. Exploiting the curative potential of adoptive T-cell therapy for cancer. Immunol Rev. 2014;257:56–71. [DOI] [PubMed] [PMC]

Barrett DM, Grupp SA, June CH. Chimeric antigen receptor- and TCR-modified T cells enter main street and wall street. J Immunol. 2015;195:755–61. [DOI] [PubMed] [PMC]

Coulie PG, Van den Eynde BJ, van der Bruggen P, Boon T. Tumour antigens recognized by T lymphocytes: at the core of cancer immunotherapy. Nat Rev Cancer. 2014;14:135–46. [DOI] [PubMed]

Melero I, Gaudernack G, Gerritsen W, Huber C, Parmiani G, Scholl S, et al. Therapeutic vaccines for cancer: an overview of clinical trials. Nat Rev Clin Oncol. 2014;11:509–24. [DOI] [PubMed]

Leko V, Rosenberg SA. Identifying and targeting human tumor antigens for T cell-based immunotherapy of solid tumors. Cancer Cell. 2020;38:454–72. [DOI] [PubMed] [PMC]

Durgeau A, Virk Y, Corgnac S, Mami-Chouaib F. Recent advances in targeting CD8 T-cell immunity for more effective cancer immunotherapy. Front Immunol. 2018;9:14. [DOI] [PubMed] [PMC]

Redwood AJ, Dick IM, Creaney J, Robinson BWS. What’s next in cancer immunotherapy? - The promise and challenges of neoantigen vaccination. Oncoimmunology. 2022;11:2038403. [DOI] [PubMed] [PMC]

10.

Boon T, Coulie PG, Van den Eynde B. Tumor antigens recognized by T cells. Immunol Today. 1997;18:267–8. [DOI] [PubMed]

11.

Echchakir H, Vergnon I, Dorothee G, Grunenwald D, Chouaib S, Mami-Chouaib F. Evidence for in situ expansion of diverse antitumor-specific cytotoxic T lymphocyte clones in a human large cell carcinoma of the lung. Int Immunol. 2000;12:537–46. [DOI] [PubMed]

12.

Pagès F, Berger A, Camus M, Sanchez-Cabo F, Costes A, Molidor R, et al. Effector memory T cells, early metastasis, and survival in colorectal cancer. N Engl J Med. 2005;353:2654–66. [DOI] [PubMed]

13.

Djenidi F, Adam J, Goubar A, Durgeau A, Meurice G, de Montpreville V, et al. CD8⁺CD103⁺ tumor-infiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients. J Immunol. 2015;194:3475–86. [DOI] [PubMed]

14.

Corgnac S, Malenica I, Mezquita L, Auclin E, Voilin E, Kacher J, et al. CD103⁺CD8⁺ T_RM cells accumulate in tumors of anti-PD-1-responder lung cancer patients and are tumor-reactive lymphocytes enriched with Tc17. Cell Rep Med. 2020;1:100127. [DOI] [PubMed] [PMC]

15.

Snyder A, Makarov V, Merghoub T, Yuan J, Zaretsky JM, Desrichard A, et al. Genetic basis for clinical response to CTLA-4 blockade in melanoma. N Engl J Med. 2014;371:2189–99. Erratum in: N Engl J Med. 2018;379:2185. [DOI] [PubMed] [PMC]

16.

Rizvi NA, Hellmann MD, Snyder A, Kvistborg P, Makarov V, Havel JJ, et al. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science. 2015;348:124–8. [DOI] [PubMed] [PMC]

17.

McGranahan N, Furness AJ, Rosenthal R, Ramskov S, Lyngaa R, Saini SK, et al. Clonal neoantigens elicit T cell immunoreactivity and sensitivity to immune checkpoint blockade. Science. 2016;351:1463–9. [DOI] [PubMed] [PMC]

18.

Gilboa E. The makings of a tumor rejection antigen. Immunity. 1999;11:263–70. [DOI] [PubMed]

19.

Marijt KA, Doorduijn EM, van Hall T. TEIPP antigens for T-cell based immunotherapy of immune-edited HLA class I^low cancers. Mol Immunol. 2019;113:43–9. [DOI] [PubMed]

20.

Leclerc M, Mezquita L, Guillebot De Nerville G, Tihy I, Malenica I, Chouaib S, et al. Recent advances in lung cancer immunotherapy: input of T-cell epitopes associated with impaired peptide processing. Front Immunol. 2019;10:1505. [DOI] [PubMed] [PMC]

21.

van der Bruggen P, Traversari C, Chomez P, Lurquin C, De Plaen E, Van den Eynde B, et al. A gene encoding an antigen recognized by cytolytic T lymphocytes on a human melanoma. Science. 1991;254:1643–7. [DOI] [PubMed]

22.

Novellino L, Castelli C, Parmiani G. A listing of human tumor antigens recognized by T cells: March 2004 update. Cancer Immunol Immunother. 2005;54:187–207. [DOI] [PubMed]

23.

Finn OJ. Human tumor antigens yesterday, today, and tomorrow. Cancer Immunol Res. 2017;5:347–54. [DOI] [PubMed] [PMC]

24.

Schiller JT, Castellsagué X, Garland SM. A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine. 2012;30:F123–38. [DOI] [PubMed] [PMC]

25.

Xing Y, Hogquist KA. T-cell tolerance: central and peripheral. Cold Spring Harb Perspect Biol. 2012;4:a006957. [DOI] [PubMed] [PMC]

26.

Melief CJ, van Hall T, Arens R, Ossendorp F, van der Burg SH. Therapeutic cancer vaccines. J Clin Invest. 2015;125:3401–12. [DOI] [PubMed] [PMC]

27.

Baumgaertner P, Jandus C, Rivals JP, Derré L, Lövgren T, Baitsch L, et al. Vaccination-induced functional competence of circulating human tumor-specific CD8 T-cells. Int J Cancer. 2012;130:2607–17. [DOI] [PubMed]

28.

Rosenberg SA, Yang JC, Schwartzentruber DJ, Hwu P, Marincola FM, Topalian SL, et al. Immunologic and therapeutic evaluation of a synthetic peptide vaccine for the treatment of patients with metastatic melanoma. Nat Med. 1998;4:321–7. [DOI] [PubMed] [PMC]

29.

Speiser DE, Baumgaertner P, Voelter V, Devevre E, Barbey C, Rufer N, et al. Unmodified self antigen triggers human CD8 T cells with stronger tumor reactivity than altered antigen. Proc Natl Acad Sci U S A. 2008;105:3849–54. Erratum in: Proc Natl Acad Sci U S A. 2008;105:10632. [DOI] [PubMed] [PMC]

30.

Quakkelaar ED, Melief CJM. Experience with synthetic vaccines for cancer and persistent virus infections in nonhuman primates and patients. Adv Immunol. 2012;114:77–106. [DOI] [PubMed]

31.

Botelho NK, Tschumi BO, Hubbell JA, Swartz MA, Donda A, Romero P. Combination of synthetic long peptides and XCL1 fusion proteins results in superior tumor control. Front Immunol. 2019;10:294. [DOI] [PubMed] [PMC]

32.

Stephens AJ, Burgess-Brown NA, Jiang S. Beyond just peptide antigens: the complex world of peptide-based cancer vaccines. Front Immunol. 2021;12:696791. [DOI] [PubMed] [PMC]

33.

Pardi N, Hogan MJ, Porter FW, Weissman D. mRNA vaccines - a new era in vaccinology. Nat Rev Drug Discov. 2018;17:261–79. [DOI] [PubMed] [PMC]

34.

Miao L, Zhang Y, Huang L. mRNA vaccine for cancer immunotherapy. Mol Cancer. 2021;20:41. [DOI] [PubMed] [PMC]

35.

Guan S, Rosenecker J. Nanotechnologies in delivery of mRNA therapeutics using nonviral vector-based delivery systems. Gene Ther. 2017;24:133–43. [DOI] [PubMed]

36.

Ott PA, Hu Z, Keskin DB, Shukla SA, Sun J, Bozym DJ, et al. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature. 2017;547:217–21. Erratum in: Nature. 2018;555:402. [DOI] [PubMed] [PMC]

37.

Sahin U, Derhovanessian E, Miller M, Kloke BP, Simon P, Löwer M, et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature. 2017;547:222–6. [DOI] [PubMed]

38.

Pulendran B, S Arunachalam P, O’Hagan DT. Emerging concepts in the science of vaccine adjuvants. Nat Rev Drug Discov. 2021;20:454–75. [DOI] [PubMed] [PMC]

39.

Wang Z, Cui K, Costabel U, Zhang X. Nanotechnology-facilitated vaccine development during the coronavirus disease 2019 (COVID-19) pandemic. Exploration (Beijing). 2022;[Epub ahead of print]. [DOI] [PubMed] [PMC]

40.

Sahin U, Oehm P, Derhovanessian E, Jabulowsky RA, Vormehr M, Gold M, et al. An RNA vaccine drives immunity in checkpoint-inhibitor-treated melanoma. Nature. 2020;585:107–12. [DOI] [PubMed]

41.

Pardi N, Hogan MJ, Naradikian MS, Parkhouse K, Cain DW, Jones L, et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J Exp Med. 2018;215:1571–88. [DOI] [PubMed] [PMC]

42.

Tenchov R, Bird R, Curtze AE, Zhou Q. Lipid nanoparticles-from liposomes to mRNA vaccine delivery, a landscape of research diversity and advancement. ACS Nano. 2021;[Epub ahead of print]. [DOI] [PubMed]

43.

Jing Z, Wang S, Xu K, Tang Q, Li W, Zheng W, et al. A potent micron neoantigen tumor vaccine GP-neoantigen induces robust antitumor activity in multiple tumor models. Adv Sci (Weinh). 2022;9:2201496. [DOI] [PubMed] [PMC]

44.

Rosenberg SA, Yang JC, Restifo NP. Cancer immunotherapy: moving beyond current vaccines. Nat Med. 2004;10:909–15. [DOI] [PubMed] [PMC]

45.

Klebanoff CA, Acquavella N, Yu Z, Restifo NP. Therapeutic cancer vaccines: are we there yet? Immunol Rev. 2011;239:27–44. [DOI] [PubMed] [PMC]

46.

Palucka K, Banchereau J. Cancer immunotherapy via dendritic cells. Nat Rev Cancer. 2012;12:265–77. [DOI] [PubMed] [PMC]

47.

Vansteenkiste JF, Cho BC, Vanakesa T, De Pas T, Zielinski M, Kim MS, et al. Efficacy of the MAGE-A3 cancer immunotherapeutic as adjuvant therapy in patients with resected MAGE-A3-positive non-small-cell lung cancer (MAGRIT): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol. 2016;17:822–35. [DOI] [PubMed]

48.

Pujol JL, De Pas T, Rittmeyer A, Vallieres E, Kubisa B, Levchenko E, et al. Safety and immunogenicity of the PRAME cancer immunotherapeutic in patients with resected non-small cell lung cancer: a phase I dose escalation study. J Thorac Oncol. 2016;11:2208–17. [DOI] [PubMed]

49.

Butts C, Socinski MA, Mitchell PL, Thatcher N, Havel L, Krzakowski M, et al.; START trial team. Tecemotide (L-BLP25) versus placebo after chemoradiotherapy for stage III non-small-cell lung cancer (START): a randomised, double-blind, phase 3 trial. Lancet Oncol. 2014;15:59–68. [DOI] [PubMed]

50.

Quoix E, Ramlau R, Westeel V, Papai Z, Madroszyk A, Riviere A, et al. Therapeutic vaccination with TG4010 and first-line chemotherapy in advanced non-small-cell lung cancer: a controlled phase 2B trial. Lancet Oncol. 2011;12:1125–33. [DOI] [PubMed]

51.

Quoix E, Lena H, Losonczy G, Forget F, Chouaid C, Papai Z, et al. TG4010 immunotherapy and first-line chemotherapy for advanced non-small-cell lung cancer (TIME): results from the phase 2b part of a randomised, double-blind, placebo-controlled, phase 2b/3 trial. Lancet Oncol. 2016;17:212–23. [DOI] [PubMed]

52.

Tosch C, Bastien B, Barraud L, Grellier B, Nourtier V, Gantzer M, et al. Viral based vaccine TG4010 induces broadening of specific immune response and improves outcome in advanced NSCLC. J Immunother Cancer. 2017;5:70. [DOI] [PubMed] [PMC]

53.

Takayama K, Sugawara S, Saijo Y, Maemondo M, Sato A, Takamori S, et al. Randomized phase II study of docetaxel plus personalized peptide vaccination versus docetaxel plus placebo for patients with previously treated advanced wild type EGFR non-small-cell lung cancer. J Immunol Res. 2016;2016:1745108. [DOI] [PubMed] [PMC]

54.

Viteri S, Vanel FR, Hilgers W, Remon J, Viteri-Ramirez G, Quoix E. Abstract 946: early signs of activity of Tedopi OSE2101, a multiple neoepitope vaccine, in a phase 3 trial in advanced lung cancer patients after failure to previous immune checkpoint inhibitors ATALANTE-1. Cancer Res. 2019;79:946. [DOI]

55.

Romero P, Banchereau J, Bhardwaj N, Cockett M, Disis ML, Dranoff G, et al. The human vaccines project: a roadmap for cancer vaccine development. Sci Transl Med. 2016;8:334ps9. [DOI] [PubMed]

56.

Hilf N, Kuttruff-Coqui S, Frenzel K, Bukur V, Stevanović S, Gouttefangeas C, et al. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature. 2019;565:240–5. Erratum in: Nature. 2019;566:E13. [DOI] [PubMed]

57.

Johanns TM, Miller CA, Liu CJ, Perrin RJ, Bender D, Kobayashi DK, et al. Detection of neoantigen-specific T cells following a personalized vaccine in a patient with glioblastoma. Oncoimmunology. 2019;8:e1561106. [DOI] [PubMed] [PMC]

58.

Keskin DB, Anandappa AJ, Sun J, Tirosh I, Mathewson ND, Li S, et al. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature. 2019;565:234–9. [DOI] [PubMed] [PMC]

59.

Cafri G, Gartner JJ, Zaks T, Hopson K, Levin N, Paria BC, et al. mRNA vaccine-induced neoantigen-specific T cell immunity in patients with gastrointestinal cancer. J Clin Invest. 2020;130:5976–88. [DOI] [PubMed] [PMC]

60.

Ding Z, Li Q, Zhang R, Xie L, Shu Y, Gao S, et al. Personalized neoantigen pulsed dendritic cell vaccine for advanced lung cancer. Signal Transduct Target Ther. 2021;6:26. [DOI] [PubMed] [PMC]

61.

Hu Z, Leet DE, Allesøe RL, Oliveira G, Li S, Luoma AM, et al. Personal neoantigen vaccines induce persistent memory T cell responses and epitope spreading in patients with melanoma. Nat Med. 2021;27:515–25. [DOI] [PubMed] [PMC]

62.

Platten M, Bunse L, Wick A, Bunse T, Le Cornet L, Harting I, et al. A vaccine targeting mutant IDH1 in newly diagnosed glioma. Nature. 2021;592:463–8. [DOI] [PubMed] [PMC]

63.

Chen Z, Zhang S, Han N, Jiang J, Xu Y, Ma D, et al. A neoantigen-based peptide vaccine for patients with advanced pancreatic cancer refractory to standard treatment. Front Immunol. 2021;12:691605. [DOI] [PubMed] [PMC]

64.

Schumacher TN, Schreiber RD. Neoantigens in cancer immunotherapy. Science. 2015;348:69–74. [DOI] [PubMed]

65.

Tran E, Turcotte S, Gros A, Robbins PF, Lu YC, Dudley ME, et al. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science. 2014;344:641–5. [DOI] [PubMed] [PMC]

66.

Lu YC, Yao X, Crystal JS, Li YF, El-Gamil M, Gross C, et al. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin Cancer Res. 2014;20:3401–10. [DOI] [PubMed] [PMC]

67.

Stevanović S, Pasetto A, Helman SR, Gartner JJ, Prickett TD, Howie B, et al. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science. 2017;356:200–5. [DOI] [PubMed] [PMC]

68.

Pritchard AL, Burel JG, Neller MA, Hayward NK, Lopez JA, Fatho M, et al. Exome sequencing to predict neoantigens in melanoma. Cancer Immunol Res. 2015;3:992–8. [DOI] [PubMed]

69.

Carreno BM, Magrini V, Becker-Hapak M, Kaabinejadian S, Hundal J, Petti AA, et al. Cancer immunotherapy. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science. 2015;348:803–8. [DOI] [PubMed] [PMC]

70.

Gubin MM, Zhang X, Schuster H, Caron E, Ward JP, Noguchi T, et al. Checkpoint blockade cancer immunotherapy targets tumour-specific mutant antigens. Nature. 2014;515:577–81. [DOI] [PubMed] [PMC]

71.

Zhang R, Yuan F, Shu Y, Tian Y, Zhou B, Yi L, et al. Personalized neoantigen-pulsed dendritic cell vaccines show superior immunogenicity to neoantigen-adjuvant vaccines in mouse tumor models. Cancer Immunol Immunother. 2020;69:135–45. [DOI] [PubMed] [PMC]

72.

McGranahan N, Swanton C. Neoantigen quality, not quantity. Sci Transl Med. 2019;11:eaax7918. [DOI] [PubMed]

73.

Bailey C, Black JRM, Reading JL, Litchfield K, Turajlic S, McGranahan N, et al. Tracking cancer evolution through the disease course. Cancer Discov. 2021;11:916–32. [DOI] [PubMed] [PMC]

74.

Turajlic S, Litchfield K, Xu H, Rosenthal R, McGranahan N, Reading JL, et al. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 2017;18:1009–21. [DOI] [PubMed]

75.

Rosenthal R, Cadieux EL, Salgado R, Bakir MA, Moore DA, Hiley CT, et al.; TRACERx consortium. Neoantigen-directed immune escape in lung cancer evolution. Nature. 2019;567:479–85. [DOI] [PubMed] [PMC]

76.

Chowell D, Morris LGT, Grigg CM, Weber JK, Samstein RM, Makarov V, et al. Patient HLA class I genotype influences cancer response to checkpoint blockade immunotherapy. Science. 2018;359:582–7. [DOI] [PubMed] [PMC]

77.

Li F, Chen C, Ju T, Gao J, Yan J, Wang P, et al. Rapid tumor regression in an Asian lung cancer patient following personalized neo-epitope peptide vaccination. Oncoimmunology. 2016;5:e1238539. [DOI] [PubMed] [PMC]

78.

Sakamoto S, Yamada T, Terazaki Y, Yoshiyama K, Sugawara S, Takamori S, et al. Feasibility study of personalized peptide vaccination for advanced small cell lung cancer. Clin Lung Cancer. 2017;18:e385–94. [DOI] [PubMed]

79.

Fang Y, Mo F, Shou J, Wang H, Luo K, Zhang S, et al. A pan-cancer clinical study of personalized neoantigen vaccine monotherapy in treating patients with various types of advanced solid tumors. Clin Cancer Res. 2020;26:4511–20. [DOI] [PubMed]

80.

McCann K, von Witzleben A, Thomas J, Wang C, Wood O, Singh D, et al. Targeting the tumor mutanome for personalized vaccination in a TMB low non-small cell lung cancer. J Immunother Cancer. 2022;10:e003821. [DOI] [PubMed] [PMC]

81.

van der Burg SH, Arens R, Ossendorp F, van Hall T, Melief CJ. Vaccines for established cancer: overcoming the challenges posed by immune evasion. Nat Rev Cancer. 2016;16:219–33. [DOI] [PubMed]

82.

Shin DS, Zaretsky JM, Escuin-Ordinas H, Garcia-Diaz A, Hu-Lieskovan S, Kalbasi A, et al. Primary resistance to PD-1 blockade mediated by JAK1/2 mutations. Cancer Discov. 2017;7:188–201. [DOI] [PubMed] [PMC]

83.

Zaretsky JM, Garcia-Diaz A, Shin DS, Escuin-Ordinas H, Hugo W, Hu-Lieskovan S, et al. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N Engl J Med. 2016;375:819–29. [DOI] [PubMed] [PMC]

84.

D’Alise AM, Leoni G, De Lucia M, Langone F, Nocchi L, Tucci FG, et al. Maximizing cancer therapy via complementary mechanisms of immune activation: PD-1 blockade, neoantigen vaccination, and Tregs depletion. J Immunother Cancer. 2021;9:e003480. [DOI] [PubMed] [PMC]

85.

Hernandez R, LaPorte KM, Hsiung S, Santos Savio A, Malek TR. High-dose IL-2/CD25 fusion protein amplifies vaccine-induced CD4⁺ and CD8⁺ neoantigen-specific T cells to promote antitumor immunity. J Immunother Cancer. 2021;9:e002865. [DOI] [PubMed] [PMC]

86.

Leclerc M, Voilin E, Gros G, Corgnac S, de Montpréville V, Validire P, et al. Regulation of antitumour CD8 T-cell immunity and checkpoint blockade immunotherapy by neuropilin-1. Nat Commun. 2019;10:3345. [DOI] [PubMed] [PMC]

87.

Baitsch L, Baumgaertner P, Devêvre E, Raghav SK, Legat A, Barba L, et al. Exhaustion of tumor-specific CD8⁺ T cells in metastases from melanoma patients. J Clin Invest. 2011;121:2350–60. [DOI] [PubMed] [PMC]

88.

Sun J, Zhang J, Hu H, Qin H, Liao X, Wang F, et al. Anti-tumour effect of neo-antigen-reactive T cells induced by RNA mutanome vaccine in mouse lung cancer. J Cancer Res Clin Oncol. 2021;147:3255–68. [DOI] [PubMed] [PMC]

89.

Peng S, Chen S, Hu W, Mei J, Zeng X, Su T, et al. Combination neoantigen-based dendritic cell vaccination and adoptive T-cell transfer induces antitumor responses against recurrence of hepatocellular carcinoma. Cancer Immunol Res. 2022;10:728–44. [DOI] [PubMed]

90.

Marincola FM, Jaffee EM, Hicklin DJ, Ferrone S. Escape of human solid tumors from T-cell recognition: molecular mechanisms and functional significance. Adv Immunol. 1999;74:181–273. [DOI] [PubMed]

91.

Abele R, Tampe R. Modulation of the antigen transport machinery TAP by friends and enemies. FEBS Lett. 2006;580:1156–63. [DOI] [PubMed]

92.

Einstein MH, Leanza S, Chiu LG, Schlecht NF, Goldberg GL, Steinberg BM, et al. Genetic variants in TAP are associated with high-grade cervical neoplasia. Clin Cancer Res. 2009;15:1019–23. [DOI] [PubMed] [PMC]

93.

Leibowitz MS, Andrade Filho PA, Ferrone S, Ferris RL. Deficiency of activated STAT1 in head and neck cancer cells mediates TAP1-dependent escape from cytotoxic T lymphocytes. Cancer Immunol Immunother. 2011;60:525–35. [DOI] [PubMed] [PMC]

94.

Garrido F, Aptsiauri N, Doorduijn EM, Garcia Lora AM, van Hall T. The urgent need to recover MHC class I in cancers for effective immunotherapy. Curr Opin Immunol. 2016;39:44–51. [DOI] [PubMed] [PMC]

95.

Durgeau A, El Hage F, Vergnon I, Validire P, de Montpréville V, Besse B, et al. Different expression levels of the TAP peptide transporter lead to recognition of different antigenic peptides by tumor-specific CTL. J Immunol. 2011;187:5532–9. [DOI] [PubMed]

96.

Leone P, Shin EC, Perosa F, Vacca A, Dammacco F, Racanelli V. MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J Natl Cancer Inst. 2013;105:1172–87. [DOI] [PubMed]

97.

Marijt KA, Blijleven L, Verdegaal EME, Kester MG, Kowalewski DJ, Rammensee HG, et al. Identification of non-mutated neoantigens presented by TAP-deficient tumors. J Exp Med. 2018;215:2325–37. [DOI] [PubMed] [PMC]

98.

El Hage F, Stroobant V, Vergnon I, Baurain JF, Echchakir H, Lazar V, et al. Preprocalcitonin signal peptide generates a cytotoxic T lymphocyte-defined tumor epitope processed by a proteasome-independent pathway. Proc Natl Acad Sci U S A. 2008;105:10119–24. [DOI] [PubMed] [PMC]

99.

Doorduijn EM, Sluijter M, Querido BJ, Oliveira CC, Achour A, Ossendorp F, et al. TAP-independent self-peptides enhance T cell recognition of immune-escaped tumors. J Clin Invest. 2016;126:784–94. [DOI] [PubMed] [PMC]

100.

Durgeau A, Virk Y, Gros G, Voilin E, Corgnac S, Djenidi F, et al. Human preprocalcitonin self-antigen generates TAP-dependent and -independent epitopes triggering optimised T-cell responses toward immune-escaped tumours. Nat Commun. 2018;9:5097. [DOI] [PubMed] [PMC]

101.

Marijt KA, Griffioen L, Blijleven L, van der Burg SH, van Hall T. Cross-presentation of a TAP-independent signal peptide induces CD8 T immunity to escaped cancers but necessitates anchor replacement. Cancer Immunol Immunother. 2022;71:289–300. [DOI] [PubMed] [PMC]

102.

Garrido G, Schrand B, Rabasa A, Levay A, D’Eramo F, Berezhnoy A, et al. Tumor-targeted silencing of the peptide transporter TAP induces potent antitumor immunity. Nat Commun. 2019;10:3773. [DOI] [PubMed] [PMC]

103.

Chowell D, Krishna C, Pierini F, Makarov V, Rizvi NA, KuoF, et al. Evolutionary divergence of HLA class I genotype impacts efficacy of cancer immunotherapy. Nat Med. 2019;25:1715–20. [DOI] [PubMed] [PMC]