Personalized Neoantigen Vaccine Shows Promise for Renal Cell Carcinoma

A recent study presented by Dr. David A. Braun, MD, PhD, at the 2025 Kidney Cancer Research Summit reveals that a personalized neoantigen vaccine may be effective for patients diagnosed with clear cell renal cell carcinoma (ccRCC). The study involved nine patients with high-risk, resectable ccRCC and demonstrates early signs of immune activation and durable responses, warranting further investigation into this innovative therapy.

Renal cell carcinoma, particularly the clear cell subtype, poses significant treatment challenges due to its complex immune landscape and relatively low mutational burden. In this context, Dr. Braun, who is an assistant professor of medicine at the Yale School of Medicine and a member of the Center of Molecular and Cellular Oncology at Yale Cancer Center, emphasized the need for novel immunotherapeutic approaches that direct the immune response more effectively.

The study involved creating personalized vaccines for the nine participants through tumor sequencing and neoantigen prediction, which resulted in vaccines composed of synthetic long peptides that incorporated up to 20 individual neoantigens from each patient's tumor. This approach aimed to enhance the immune response by reducing competition among different neoantigens, thereby increasing the likelihood of immune recognition.

"The basic question was: Are the T cells reacting to these neoantigens and capable of recognition?" Braun stated during his presentation. Prior to vaccination, most patients exhibited undetectable levels of neoantigen immunity. Following vaccination, however, significant neoantigen-specific T-cell responses were observed in all treated patients.

Braun's research aligns with previous findings that have shown the potential efficacy of neoantigen-directed therapies across various cancer types, including melanoma and glioblastoma. However, he acknowledged that kidney cancer presents unique challenges due to its modest mutation burden, necessitating tailored approaches to vaccine design.

The trial design included a two-phase vaccination regimen: a priming phase to activate T cells, followed by a boosting phase to promote long-term immune memory. This innovative approach demonstrated that 7 out of the 9 patients generated detectable levels of vaccine-specific T cells that reacted against their tumors. Impressively, at a median follow-up of 40.2 months, none of the participants experienced a recurrence of their disease.

Despite these promising results, Braun noted that the small sample size represents a limitation of the study, and further research is necessary to validate these findings. The next phase of the clinical investigation, the INterpath-004 trial (NCT06307431), aims to assess the combination of the mRNA-based neoantigen vaccine with pembrolizumab, a checkpoint inhibitor, in a larger cohort of renal cell carcinoma patients.

This study underscores the potential of personalized cancer vaccines in improving patient outcomes in renal cell carcinoma, particularly for those at high risk of recurrence. As the field of cancer immunotherapy continues to evolve, the findings from this research may pave the way for more effective treatment strategies, ultimately enhancing survival rates and quality of life for patients battling this challenging disease.