Therapeutic vaccination for active induction of T cell immunity against cancer, ready for a rich harvest after 40 years.

Therapeutic vaccines include DNA, mRNA, protein-loaded antigen-presenting cell, synthetic long peptide (SLP) and recombinant virus platforms. Only two therapeutic vaccines for neoplastic disease were approved by the Food and Drug Administration in the past 40 years: sipuleucel-T, approved in 2010 for hormone-resistant metastatic prostate cancer and targeting prostate acid phosphatase; and zopapogene imadenovec, approved in 2025 for recurrent respiratory papillomatosis, a rare, non-malignant but often invalidating disease caused by human papillomavirus (HPV) type 6 or type 11. In the last decade, DNA, mRNA and SLP vaccines directed against mutation-derived neoantigens have shown strong immunogenicity for T cells and clinical activity with or without additional immune checkpoint inhibition. Vaccine monotherapy is effective in premalignant disorders caused by high-risk HPV16 and virus-negative colonic polyps. Treatment of bulky or recurrent/metastatic (R/M) disease requires combination with surgery and/or chemotherapy or combination with an immune checkpoint inhibitor such as PD-1 blocker. In a recent study, adjuvant treatment with neoantigen-specific mRNA vaccine plus PD-1 blocker led to less melanoma recurrence than PD-1 blocker alone. In another randomized study, patients with R/M HPV16+ head and neck cancer only benefited from the combination of HPV16-specific SLP vaccine and a PD-1 blocker if they had high pretreatment PD-L1 biomarker expression in cancer tissue. Increasingly, biomarker-guided therapy is recommended.