Abstract
The results of genomic and molecular profiling of cancer patients can be effectively applied to immunotherapy agents, including immune checkpoint inhibitors, to select the most appropriate treatment. In addition, accurate prediction of neoantigens facilitates the development of individualized cancer vaccines and T-cell therapy. This review summarizes the biomarker(s) predicting responses to immune checkpoint inhibitors and focuses on current strategies to identify and isolate neoantigen-reactive T cells as well as the clinical development of neoantigen-based therapeutics. The results suggest that maximal T-cell stimulation and expansion can be achieved with combination therapies that enhance antigen-presenting cells' function and optimal T-cell priming in lymph nodes.
References
- 1. . The ways of isolating neoantigen-specific T cells. Front. Oncol. 10, 1347 (2020).
- 2. . Nivolumab and pembrolizumab as immune-modulating monoclonal antibodies targeting the PD-1 receptor to treat melanoma. Expert Rev. Anticancer Ther. 15(9), 981–993 (2015).
- 3. . Recent developments of RNA-based vaccines in cancer immunotherapy. Expert Opin. Biol. Ther. 21(2), 201–218 (2021).
- 4. . Cellular immunotherapy in gastric cancer: adoptive cell therapy and dendritic cell-based vaccination. Immunotherapy 14(6), 475–488 (2022).
- 5. . Personalized immunotherapy in cancer precision medicine. Cancer Biol. Med. 18(4), 955 (2021).
- 6. Neoantigen identification strategies enable personalized immunotherapy in refractory solid tumors. J. Clin. Investig. 129(5), 2056–2070 (2019).
- 7. . Advances in the development of personalized neoantigen-based therapeutic cancer vaccines. Nat. Rev. Clin. Oncol. 18(4), 215–229 (2021).
- 8. . Safety and efficacy of personalized cancer vaccines in combination with immune checkpoint inhibitors in cancer treatment. Front. Oncol. 11, 663264 (2021).
- 9. . Neoantigens: promising targets for cancer therapy. Signal. Transduct. Target. Ther. 8(1), 9 (2023).
- 10. . Neoantigens in cancer immunotherapy. Science 348(6230), 69–74 (2015).
- 11. . Harnessing tumor mutations for truly individualized cancer vaccines. Annu. Rev. Med. 70, 395–407 (2019).
- 12. Insertion-and-deletion-derived tumour-specific neoantigens and the immunogenic phenotype: a pan-cancer analysis. Lancet Oncol. 18(8), 1009–1021 (2017).
- 13. Immunogenic neoantigens derived from gene fusions stimulate T cell responses. Nat. Med. 25(5), 767–775 (2019).
- 14. Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer. Nature 551(7681), 512–516 (2017).
- 15. Genomic correlates of immune-cell infiltrates in colorectal carcinoma. Cell Rep. 15(4), 857–865 (2016).
- 16. Association of polymerase e-mutated and microsatellite-instable endometrial cancers with neoantigen load, number of tumor-infiltrating lymphocytes, and expression of PD-1 and PD-L1. JAMA Oncol. 1(9), 1319–1323 (2015).
- 17. Cytolytic activity correlates with the mutational burden and deregulated expression of immune checkpoints in colorectal cancer. J. Exp. Clin. Cancer Res. 38(1), 364 (2019).
- 18. . Immunopharmacogenomics towards personalized cancer immunotherapy targeting neoantigens. Cancer Sci. 109(3), 542–549 (2018).
- 19. The immune epitope database (IEDB) 3.0. Nucleic Acids Res. 43(D1), D405–D412 (2015).
- 20. Efficient identification of mutated cancer antigens recognized by T cells associated with durable tumor regressions. Clin. Cancer Res. 20(13), 3401–3410 (2014).
- 21. . The efficacy of tumor mutation burden as a biomarker of response to immune checkpoint inhibitors. Int. J. Mol. Sci. 24(7), 6710 (2023).
- 22. Whole-exome sequencing of muscle-invasive bladder cancer identifies recurrent mutations of UNC5C and prognostic importance of DNA repair gene mutations on survival. Clin. Cancer Res. 20(24), 6605–6617 (2014).
- 23. Low T-cell receptor diversity, high somatic mutation burden, and high neoantigen load as predictors of clinical outcome in muscle-invasive bladder cancer. Eur. Urol. Focus 2(4), 445–452 (2016).
- 24. . Integrated analysis of somatic mutations and immune microenvironment of multiple regions in breast cancers. Oncotarget 8(37), 62029 (2017).
- 25. Integrated analysis of somatic mutations and immune microenvironment in malignant pleural mesothelioma. Oncoimmunology 6(2), e1278330 (2017).
- 26. Immunogenomic profiles associated with response to neoadjuvant chemoradiotherapy in patients with rectal cancer. Br. J. Surg. 106(10), 1381–1392 (2019).
- 27. T-cell complexity and density are associated with sensitivity to neoadjuvant chemoradiotherapy in patients with rectal cancer. Cancer Immunol. Immunother. 70(2), 509–518 (2021).
- 28. 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(12), 13587 (2016).
- 29. Neoantigen load, antigen presentation machinery, and immune signatures determine prognosis in clear cell renal cell carcinomaneoantigens and immune signature of ccRCC patients. Cancer Immunol. Res. 4(5), 463–471 (2016).
- 30. . Tumor mutation burden in the prognosis and response of lung cancer patients to immune-checkpoint inhibition therapies. Transl. Oncol. 38, 101788 (2023).
- 31. Mutational landscape determines sensitivity to PD-1 blockade in non–small cell lung cancer. Science 348(6230), 124–128 (2015).
- 32. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257), 207–211 (2015).
- 33. PD-1 blockade in tumors with mismatch-repair deficiency. N. Engl. J. Med. 372(26), 2509–2520 (2015).
- 34. . High expression of immune checkpoints is associated with the TIL load, mutation rate and patient survival in colorectal cancer. Int. J. Oncol. 57(1), 237–248 (2020).
- 35. Tumor mutational burden as an independent predictor of response to immunotherapy in diverse cancers. Mol. Cancer Ther. 16(11), 2598–2608 (2017).
- 36. Tumor mutational load predicts survival after immunotherapy across multiple cancer types. Nat. Genet. 51(2), 202–206 (2019).
- 37. Tumor mutational burden standardization initiatives: recommendations for consistent tumor mutational burden assessment in clinical samples to guide immunotherapy treatment decisions. Genes Chromosomes Cancer 58(8), 578–588 (2019).
- 38. Neoantigen responses, immune correlates, and favorable outcomes after ipilimumab treatment of patients with prostate cancer. Sci. Transl. Med. 12(537), eaaz3577 (2020).
- 39. Genomic correlates of response to immune checkpoint blockade in microsatellite-stable solid tumors. Nat. Genet. 50(9), 1271–1281 (2018).
- 40. . FDA approval summary: pembrolizumab for the treatment of microsatellite instability-high solid tumors. Clin. Cancer Res. 25(13), 3753–3758 (2019).
- 41. . Response to PD-1 blockade in microsatellite stable metastatic colorectal cancer harboring a POLE mutation. J. Natl. Compr. Canc. Netw. 15(2), 142–147 (2017).
- 42. Mutations associated with acquired resistance to PD-1 blockade in melanoma. N. Engl. J. Med. 375(9), 819–829 (2016).
- 43. Loss of PTEN promotes resistance to T Cell-mediated immunotherapy. Cancer Discov. 6(2), 202–216 (2016).
- 44. Significant differences in T cell receptor repertoires in lung adenocarcinomas with and without epidermal growth factor receptor mutations. Cancer Sci. 110(3), 867–874 (2019).
- 45. STK11/LKB1 deficiency promotes neutrophil recruitment and proinflammatory cytokine production to suppress T-cell activity in the lung tumor microenvironment. Cancer Res. 76(5), 999–1008 (2016).
- 46. Pan-tumor genomic biomarkers for PD-1 checkpoint blockade-based immunotherapy. Science 362(6411), eaar3593 (2018).
- 47. Intratumoral expression levels of PD-L1, GZMA, and HLA-A along with oligoclonal T cell expansion associate with response to nivolumab in metastatic melanoma. Oncoimmunology 5(9), e1204507 (2016).
- 48. Peripheral T cell receptor repertoire features predict durable responses to anti-PD-1 inhibitor monotherapy in advanced renal cell carcinoma. Oncoimmunology 10(1), 1862948 (2021).
- 49. Removal of N-linked glycosylation enhances PD-L1 detection and predicts anti-PD-1/PD-L1 therapeutic efficacy. Cancer cell 36(2), 168–178.e164 (2019).
- 50. Prospective analysis of adoptive TIL therapy in patients with metastatic melanoma: response, impact of anti-CTLA4, and biomarkers to predict clinical outcome. Clin. Cancer Res. 24(18), 4416–4428 (2018).
- 51. Long-lasting complete responses in patients with metastatic melanoma after adoptive cell therapy with tumor-infiltrating lymphocytes and an attenuated IL2 regimen. Clin. Cancer Res. 22(15), 3734–3745 (2016).
- 52. . ‘Final common pathway' of human cancer immunotherapy: targeting random somatic mutations. Nat. Immunol. 18(3), 255–262 (2017).
- 53. Mining exomic sequencing data to identify mutated antigens recognized by adoptively transferred tumor-reactive T cells. Nat. Med. 19(6), 747 (2013).
- 54. Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy. JCI Insight 3(19), e122467 (2018).
- 55. Enhancing CAR-T cell functionality in a patient-specific manner. Nat. Commun. 14(1), 506 (2023).
- 56. . CAR-T cell and personalized medicine. Adv. Exp. Med. Biol. 1168, 131–145 (2019).
- 57. Engineered TCR-T cell immunotherapy in anticancer precision medicine: pros and cons. Front. immunol. 12, 658753 (2021).
- 58. The response of autologous T cells to a human melanoma is dominated by mutated neoantigens. Proc. Natl Acad. Sci. USA 102(44), 16013–16018 (2005).
- 59. Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes. J. Clin. Investig. 125(10), 3981–3991 (2015).
- 60. Memory T cells targeting oncogenic mutations detected in peripheral blood of epithelial cancer patients. Nat. Commun. 10(1), 1–9 (2019).
- 61. T-cell libraries allow simple parallel generation of multiple peptide-specific human T-cell clones. J. Immunol. Methods 430, 43–50 (2016).
- 62. . A library-based screening method identifies neoantigen-reactive T cells in peripheral blood prior to relapse of ovarian cancer. Oncoimmunology 7(1), e1371895 (2018).
- 63. Durable complete responses in heavily pretreated patients with metastatic melanoma using T-cell transfer immunotherapy. Clin. Cancer Res. 17(13), 4550–4557 (2011).
- 64. Durable complete response from metastatic melanoma after transfer of autologous T cells recognizing 10 mutated tumor antigens. Cancer Immunol. Res. 4(8), 669–678 (2016).
- 65. Mutated PPP1R3B is recognized by T cells used to treat a melanoma patient who experienced a durable complete tumor regression. J. Immunol. 190(12), 6034–6042 (2013).
- 66. Landscape of immunogenic tumor antigens in successful immunotherapy of virally induced epithelial cancer. Science 356(6334), 200–205 (2017).
- 67. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344(6184), 641–645 (2014).
- 68. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375(23), 2255–2262 (2016).
- 69. Immune recognition of somatic mutations leading to complete durable regression in metastatic breast cancer. Nat. Med. 24(6), 724–730 (2018).
- 70. A dendritic cell vaccine increases the breadth and diversity of melanoma neoantigen-specific T cells. Science 348(6236), 803–808 (2015).
- 71. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature 547(7662), 222–226 (2017).
- 72. An immunogenic personal neoantigen vaccine for patients with melanoma. Nature 547(7662), 217–221 (2017).
- 73. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565(7738), 234–239 (2019).
- 74. Actively personalized vaccination trial for newly diagnosed glioblastoma. Nature 565(7738), 240–245 (2019).
- 75. Personalized cancer vaccine effectively mobilizes antitumor T cell immunity in ovarian cancer. Sci. Transl. Med. 10(436), eaao5931 (2018).
- 76. 413 GEN-009, a personalized neoantigen vaccine, elicits robust immune responses in individuals with advanced or metastatic solid tumors. J. Immunother. Cancer 8(Suppl. 3), (2020).
- 77. 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).
- 78. 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), (2019).
- 79. 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(2), 347–362.e324 (2020).
- 80. An open-label, phase Ib study of NEO-PV-01+ adjuvant with nivolumab in patients with melanoma, non-small cell lung carcinoma, or transitional cell carcinoma of the bladder. J. Clin. Oncol. 35(Suppl. 15), (2017).
- 81. . A phase Ia study to evaluate RO7198457, an individualized neoantigen specific immunotherapy (iNeST), in patients with locally advanced or metastatic solid tumors. Presented at: Proc. Am. Assoc. Cancer Res. 80(Suppl. 16), CT169 (2020).
- 82. 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(Suppl. 16), CT301 (2020).
- 83. 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), 2523–2523 (2019).
- 84. Neoantigen vaccine: an emerging tumor immunotherapy. Mol. Cancer 18(1), 1–14 (2019).
- 85. . Developing neoantigen-targeted T cell-based treatments for solid tumors. Nat. Med. 25(10), 1488–1499 (2019).
- 86. Enhanced CAR-T cell activity against solid tumors by vaccine boosting through the chimeric receptor. Science 365(6449), 162–168 (2019).
- 87. . Biomaterials assisted construction of neoantigen vaccines for personalized cancer immunotherapy. Expert Opin. Drug Deliv. 20(3), 323–333 (2023).
- 88. In situ antigen‐capturing nanochaperone toward personalized nanovaccine for cancer immunotherapy. Small 18(32), 2203100 (2022).
- 89. . Dendritic cell derived exosomes loaded neoantigens for personalized cancer immunotherapies. J. Control Release 353, 423–433 (2023).
- 90. A nanovaccine for antigen self-presentation and immunosuppression reversal as a personalized cancer immunotherapy strategy. Nat. Nanotechnol. 17(5), 531–540 (2022).
- 91. . Neoantigens: unleashing the power of personalized cancer immunotherapy. J. Oncol. Transl. Res. 9(1), (2023).