Safety and efficacy of mutant neoantigen-specific T-cell treatment combined anti-PD-1 therapy in stage IV solid tumors
Abstract
Aims: This trial explored the safety and efficacy of neoantigen-specific T cells (Nas-Ts) combined with anti-PD-1 (Nas-T + anti-PD-1). Patients & methods: This non-randomized trial recruited participants with solid tumors treated with at least two prior systemic treatment lines. For comparison, 1:1-matched controls who received anti-PD-1 alone were recruited. The primary end point was safety. Results: 15 participants were enrolled in the Nas-T + anti-PD-1 group, the objective response rate was 33.3%, and the disease control rate was 93.3%. The median progression-free survival was significantly different between the Nas-T + anti-PD-1 and control groups (13.8 vs 4.2 months; p = 0.024), but no difference in overall survival was found (p = 0.126). The most common adverse events were maculopapular skin reaction (53.3%), rash (53.3%), hepatotoxicity (53.3%) and fever (53.3%) in the Nas-T + anti-PD-1 group. No serious safety issues were experienced. Conclusion: Nas-Ts combined with anti-PD-1 could be more effective than anti-PD-1 alone in prolonging progression-free survival, with good safety.
Plain language summary
Cancer immune escape is a major mechanism allowing cancer cells to avoid treatments, and PD-1 is one of those mechanisms. Nevertheless, therapies targeting PD-1 are still somewhat unsatisfactory. In this trial, we explored the safety and efficacy of mutant neoantigen-specific T cells (Nas-Ts) as adoptive cell immunotherapy individualized for each tumor, combined with an anti-PD-1 regimen (Nas-T + anti-PD-1). We recruited participants with solid tumors treated with at least two prior systemic treatment lines: 15 participants were enrolled in the Nas-T + anti-PD-1 group and 15 more in the control group. After the last follow-up, the percentage of patients on whom a therapy had some defined effect as well as the percentage of patients with advanced and metastatic cancer who achieved complete response was significantly higher for those who received Nas-T + anti-PD-1. No serious safety issues were experienced. This study confirmed that Nas-Ts combined with anti-PD-1 could be more effective than anti-PD-1 alone in delaying progression, with good safety.
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References
- 1. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin. 68(6), 394–424 (2018).
- 2. . Cancer statistics, 2020. CA Cancer J. Clin. 70(1), 7–30 (2020).
- 3. Immune evasion in cancer: mechanistic basis and therapeutic strategies. Semin. Cancer Biol. 35(Suppl.), 185–198 (2015). •• Provides a description of mechanisms of immune evasion of cancer cells and the potential strategies to counter it.
- 4. . Immune escape mechanisms and future prospects for immunotherapy in neuroblastoma. Biomed. Res. Int. 18, 1812535 (2018).
- 5. . The PD-1 pathway in tolerance and autoimmunity. Immunol. Rev. 236, 219–242 (2010).
- 6. . The role of the PD-1 pathway in autoimmunity and peripheral tolerance. Ann. NY Acad. Sci. 1217(1), 45–59 (2011). •• Provides a description of the role of PD-1 in the immune system.
- 7. . De-novo and acquired resistance to immune checkpoint targeting. Lancet Oncol. 18(12), e731–e741 (2017). •• Describes the reasons for resistance to immune checkpoint inhibitors.
- 8. . PD-L1 expression in human cancers and its association with clinical outcomes. Onco. Targets Ther. 9, 5023–5039 (2016).
- 9. . PD-L1 expression in cancer patients receiving anti PD-1/PD-L1 antibodies: a systematic review and meta-analysis. Crit. Rev. Oncol. Hematol. 100, 88–98 (2016).
- 10. . Immune checkpoint proteins: a new therapeutic paradigm for cancer – preclinical background: CTLA-4 and PD-1 blockade. Semin. Oncol. 37(5), 430–439 (2010).
- 11. . Acquired mechanisms of immune escape in cancer following immunotherapy. Genome Med. 10(1), 87 (2018). •• Also describes the reasons for resistance to immune checkpoint inhibitors.
- 12. . Progress and challenges in precise treatment of tumors with PD-1/PD-L1 blockade. Front. Immunol. 11, 339 (2020).
- 13. . Tumor immunology and immune checkpoint inhibitors in non-small cell lung cancer. Tuberc. Respir. Dis. (Seoul) 81(1), 29–41 (2018).
- 14. A pilot trial using lymphocytes genetically engineered with an NY-ESO-1-reactive T-cell receptor: long-term follow-up and correlates with response. Clin. Cancer Res. 21(5), 1019–1027 (2015).
- 15. PLAC1-specific TCR-engineered T cells mediate antigen-specific antitumor effects in breast cancer. Oncol. Lett. 15(4), 5924–5932 (2018).
- 16. Single variable domains from the T cell receptor beta chain function as mono- and bifunctional CARs and TCRs. Sci. Rep. 9(1), 17291 (2019).
- 17. Efficient identification of neoantigen-specific T-cell responses in advanced human ovarian cancer. J. Immunother. Cancer 7(1), 156 (2019).
- 18. Mutation-derived neoantigen-specific T-cell responses in multiple myeloma. Clin. Cancer Res. 26(2), 450–464 (2020).
- 19. T-cell transfer therapy targeting mutant KRAS in cancer. N. Engl. J. Med. 375(23), 2255–2262 (2016).
- 20. Cancer immunotherapy based on mutation-specific CD4+ T cells in a patient with epithelial cancer. Science 344(6184), 641–645 (2014).
- 21. Enhanced detection of neoantigen-reactive T cells targeting unique and shared oncogenes for personalized cancer immunotherapy. JCI Insight 3(19), e122467 (2018).
- 22. CD30-targeted CAR T cells show promise in pretreated Hodgkin lymphoma. Cancer Discov. 10(9), 1253 (2020).
- 23. Neoantigen vaccine generates intratumoral T cell responses in phase Ib glioblastoma trial. Nature 565(7738), 234–239 (2019).
- 24. . An update on adoptive T-cell therapy and neoantigen vaccines. Am. Soc. Clin. Oncol. Educ. Book 39, e70–e78 (2019).
- 25. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer 45(2), 228–247 (2009).
- 26. Local mutational diversity drives intratumoral immune heterogeneity in non-small cell lung cancer. Nat. Commun. 9(1), 5361 (2018).
- 27. Diversity index of mucosal resident T lymphocyte repertoire predicts clinical prognosis in gastric cancer. Oncoimmunology 4(4), e1001230 (2015).
- 28. Peripheral T cell receptor diversity is associated with clinical outcomes following ipilimumab treatment in metastatic melanoma. J. Immunother. Cancer 3, 23 (2015).
- 29. T cells targeting carcinoembryonic antigen can mediate regression of metastatic colorectal cancer but induce severe transient colitis. Mol. Ther. 19(3), 620–626 (2011).
- 30. . Dendritic cell-based vaccines: shining the spotlight on signal 3. Oncoimmunology 2(11), e26512 (2013).
- 31. Antitumor activity associated with prolonged persistence of adoptively transferred NY-ESO-1 (c259)T cells in synovial sarcoma. Cancer Discov. 8(8), 944–957 (2018).
- 32. Phase I study of chimeric antigen receptor-modified T cells in patients with EGFR-positive advanced biliary tract cancers. Clin. Cancer Res. 24(6), 1277–1286 (2018).
- 33. Phase I study of chimeric antigen receptor modified T cells in treating HER2-positive advanced biliary tract cancers and pancreatic cancers. Protein Cell 9(10), 838–847 (2018).
- 34. Cancer regression and neurological toxicity following anti-MAGE-A3 TCR gene therapy. J. Immunother. 36(2), 133–151 (2013).
- 35. Cancer regression in patients after transfer of genetically engineered lymphocytes. Science 314(5796), 126–129 (2006).
- 36. Tumor regression in patients with metastatic synovial cell sarcoma and melanoma using genetically engineered lymphocytes reactive with NY-ESO-1. J. Clin. Oncol. 29(7), 917–924 (2011).
- 37. Adoptive transfer of MAGE-A4 T-cell receptor gene-transduced lymphocytes in patients with recurrent esophageal cancer. Clin. Cancer Res. 21(10), 2268–2277 (2015).
- 38. Activity of mesothelin-specific chimeric antigen receptor T cells against pancreatic carcinoma metastases in a phase 1 trial. Gastroenterology 155(1), 29–32 (2018).
- 39. Safety, tumor trafficking and immunogenicity of chimeric antigen receptor (CAR)-T cells specific for TAG-72 in colorectal cancer. J. Immunother. Cancer 5, 22 (2017).
- 40. Blockade of programmed death 1 augments the ability of human T cells engineered to target NY-ESO-1 to control tumor growth after adoptive transfer. Clin. Cancer. Res. 22(2), 436–447 (2016).
- 41. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230), 124–128 (2015).
- 42. . T-cell receptor profiling in cancer. Mol. Oncol. 9(10), 2063–2070 (2015).
- 43. Sensitive and frequent identification of high avidity neo-epitope specific CD8 (+) T cells in immunotherapy-naive ovarian cancer. Nat. Commun. 9(1), 1092 (2018).
- 44. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515(7528), 568–571 (2014).
- 45. Peripheral blood TCR repertoire profiling may facilitate patient stratification for immunotherapy against melanoma. Cancer Immunol. Res. 7(1), 77–85 (2019).
- 46. Clinical features of acquired resistance to anti-PD-1 therapy in advanced melanoma. Cancer Immunol. Res. 5(5), 357–362 (2017).
- 47. Comparative effectiveness of pembrolizumab vs. nivolumab in patients with recurrent or advanced NSCLC. Sci. Rep. 10(1), 13160 (2020).
- 48. . Safety and efficacy of anti-PD-1 monoclonal antibodies in patients with relapsed or refractory lymphoma: a meta-analysis of prospective clinic trails. Front. Pharmacol. 10, 387 (2019).