Individualised neoantigen cancer vaccine therapy

Active specific immunotherapy with personalised cancer vaccines has been investigated for more than 40 years. In the 1970s, cancer vaccines by injection of patient-derived autologous tumour cells or tumour lysates were given to patients and achieved modest outcomes. For example, Laucius and colleagues reported that a vaccine consisting of autologous, irradiated melanoma cells mixed with adjuvant Bacillus Calmette-Guérin resulted in regression of metastasis in four of 18 participants with surgically incurable melanoma. 1 Laucius JF Bodurtha AJ Mastrangelo JM Bellet RE A phase II study of autologous irradiated tumor cells plus BCG in patients with metastatic malignant melanoma. Cancer. 1977; 40: 2091-2093 Crossref PubMed Scopus (36) Google Scholar Additionally, the concept of neoantigens (new antigenic determinants) was investigated by Berd and colleagues by modifying autologous cancer cells with the hapten, dinitrophenyl, to induce an immune response against melanoma cancer cells. 2 Berd D Murphy G Maguire Jr, HC Mastrangelo MJ Immunization with haptenized, autologous tumor cells induces inflammation of human melanoma metastases. Cancer Res. 1991; 51: 2731-2734 PubMed Google Scholar They treated 214 patients with clinical stage IIIB–C melanoma with adjuvant dinitrophenyl-modified autologous cancer cell vaccine and noted improvement of 5-year overall survival in patients who developed delayed type hypersensitivity to unmodified melanoma cells compared with those without delayed type hypersensitivity response (5-year overall survival rate; 59·3% vs 29·3%; p<0·001). 3 Berd D Sato T Maguire Jr, HC Kairys J Mastrangelo MJ Immunopharmacologic analysis of an autologous, hapten-modified human melanoma vaccine. J Clin Oncol. 2004; 22: 403-415 Crossref PubMed Scopus (121) Google Scholar The first US Food and Drug Administration approval for a therapeutic cancer vaccine in 2010 was for an autologous dendritic cell-based vaccine loaded with a prostatic acid phosphatase-granulocyte-macrophage colony-stimulating factor fusion protein for advanced castrate-resistant prostate cancer. 4 Cheever MA Higano CS PROVENGE (Sipuleucel-T) in prostate cancer: the first FDA-approved therapeutic cancer vaccine. Clin Cancer Res. 2011; 17: 3520-3526 Crossref PubMed Scopus (526) Google Scholar However, with the approval of immune checkpoint inhibitors in the past decade, the focus of cancer immunotherapy shifted from individualised cancer vaccines to non-personalised treatments. Although immune checkpoint inhibitors treatment resulted in long-lasting responses in a small number of patients with cancer, it also highlighted the need to further improve efficacy and minimise immune-related toxicity. 5 Johnson DB Nebhan CA Moslehi JJ Balko JM Immune-checkpoint inhibitors: long-term implications of toxicity. Nat Rev Clin Oncol. 2022; 19: 254-267 Crossref PubMed Scopus (296) Google Scholar , 6 Friedrich M Immunotherapy 2.0: improving the response to checkpoint inhibitors. JAMA. 2019; 321: 131-133 Crossref PubMed Scopus (12) Google Scholar Individualised neoantigen therapy mRNA-4157 (V940) plus pembrolizumab versus pembrolizumab monotherapy in resected melanoma (KEYNOTE-942): a randomised, phase 2b studyAdjuvant mRNA-4157 plus pembrolizumab prolonged recurrence-free survival versus pembrolizumab monotherapy in patients with resected high-risk melanoma and showed a manageable safety profile. These results provide evidence that an mRNA-based individualised neoantigen therapy might be beneficial in the adjuvant setting. Full-Text PDF