Personalized Cancer Vaccines: What Challenges Remain?

Personalized cancer vaccines are generating renewed interest as new clinical data emerge for melanoma and head and neck cancers. These vaccines target neoantigens selected from mutations specific to each patient’s tumor. In melanoma, Moderna’s messenger RNA (mRNA) vaccine intismeran, combined with pembrolizumab, met the primary endpoint of recurrence-free survival and a key secondary endpoint of distant metastasis-free survival in a phase 3 trial. In head and neck cancer, the personalized vaccine TG4050 induced durable immune responses in a phase 1 trial, although its efficacy still needs to be confirmed.Recent advances have brought further attention to this approach. Recent clinical data include the phase 3 results reported by Moderna and Merck for intismeran in melanoma and the first clinical data on TG4050, developed by the French biotechnology company Transgene for head and neck cancer. Although the two vaccines use different technologies, both are individually designed using mutations identified in each patient’s tumor.Targeting Tumor MutationsUnlike prophylactic vaccines, personalized therapeutic vaccines are not intended to prevent the onset of cancer but rather to stimulate an immune response against a tumor that has already been diagnosed. In the intismeran and TG4050 trials, the vaccines were administered after the initial treatment to prevent recurrence.After sequencing a tumor sample, the identified mutations can be analyzed using computer algorithms or AI to predict which neoantigens are likely to trigger an immune response.A patient-specific vaccine is then produced: The sequences encoding the selected neoantigens are assembled into synthetic mRNA, which is typically encapsulated in lipid nanoparticles. After administration, the mRNA induces a T-cell response capable of recognizing tumor cells that express the targeted neoantigens.Other platforms can also be used to deliver neoantigens, including peptides, DNA, dendritic cells, and viral vectors.On August 19, 2026, Moderna and Merck announced that intismeran, an mRNA vaccine, combined with pembrolizumab, prolonged recurrence-free survival compared with pembrolizumab alone in patients with completely resected, high-risk melanoma.The phase 3 INTerpath-001 trial used a double-blind, placebo-controlled design and included more than 1100 patients. Following tumor analysis, the intismeran vaccine was individually designed to encode up to 34 neoantigens. Pembrolizumab simultaneously blocks the PD-1 immune checkpoint, helping T cells target tumor cells.Commenting on the announcement, several experts described the findings as important developments in the field. This was the first phase 3 trial of a personalized mRNA cancer vaccine to be reported as meeting its primary endpoint. It also reinforced the findings from the phase 2b KEYNOTE-942 trial, which included 157 patients.However, detailed efficacy and safety data have not yet been published.Another TechnologyTransgene is developing TG4050, which uses a modified vaccinia Ankara viral vector encoding up to 30 neoantigens selected for each patient with the help of AI.The randomized phase 1 trial, published in Nature Communications, included 33 patients with locally advanced human papillomavirus-negative head and neck squamous cell carcinoma who had a complete response after surgery and adjuvant treatment. Patients either received TG4050 immediately or were placed under surveillance, with vaccination planned if cancer recurrence occurred.In the per-protocol analysis, none of the 16 patients who received immediate vaccination experienced recurrence after a median follow-up of 30 months compared with 3 of 16 patients under surveillance. After a median follow-up period of 41 months, no additional recurrences occurred. T-cell responses directed against neoantigens were detected in 73.3% of vaccinated patients and persisted for more than 1 year in some patients. No vaccine-related adverse events of grade ≥ 3 were reported.These findings were encouraging, but they will need to be confirmed by the ongoing phase 2 trial.Further Progress NeededDespite these clinical advances, several important questions remain unanswered. The selection of neoantigens that are genuinely immunogenic remains complex, even with advances in AI. The time and cost required to manufacture individualized vaccines, along with tumor heterogeneity and evolution, also present significant challenges.Further improvements are still needed, particularly in the following aspects:Understanding how long induced immune responses persist, how effectively immune cells infiltrate tumors, and how long-term recurrence can be preventedIdentification of biomarkers that can predict the intensity and duration of the immune response and accelerate clinical evaluationImprovements in delivery systems, particularly lipid nanoparticles, to protect mRNA from degradation and promote its entry into the cellsThis story was translated from Univadis France, part of the Medscape Professional Network.