Neoantigen Vaccine Shows Promise In RCC-Mutated Renal Cell Carcinoma

Investigators created personalized vaccines for 9 patients with high-risk, resectable ccRCC.

Personalized neoantigen vaccines showed early signs of immune activation and durable response in certain patients with clear cell renal cell carcinal (ccRCC), necessitating further research into this therapy, explained David A. Braun, MD, PhD, during a presentation at the 2025 Kidney Cancer Research Summit.

Braun described the rationale and design of a phase 1 trial (NCT02950766) investigating the efficacy of personalized neoantigen vaccines in patients with high-risk, resectable ccRCC; key antitumor strengths of this vaccine; and why the minimal residual disease (MRD) setting may be most optimal for developing therapeutic vaccines for patients with kidney cancer and other diseases with relatively low mutational burdens.

Braun is an assistant professor of medicine (medical oncology) and the Louis Goodman and Alfred Gilman Yale Scholar at the Yale School of Medicine, and a member of the Center of Molecular and Cellular Oncology at Yale Cancer Center in New Haven, Connecticut.

Spotlighting the Promise of Neoantigen Vaccines in RCC

Braun framed his presentation with a glance at the mechanisms of antitumor immunity in kidney cancer. He used the analogy of a car, explaining that the goal of cancer therapy is to drive CD8-positive T cells toward the tumor as quickly and accurately as possible. He noted that historically, this goal has been achieved through immune activation strategies, such as immune checkpoint inhibitors, which he likened to releasing the brakes of the car, as well as novel cytokine and immune agonists, which are comparable to pressing the gas pedals. However, he emphasized that propelling the next generation of kidney cancer therapies will rely on immune navigation approaches, such as antigen-directed therapies, which steer the immune system in the optimal direction.

“Personalized cancer vaccines are an ideal example of how to do that,” Braun stated.

Braun and colleagues saw the potential for neoantigens as effective targets for antitumor immunity and T-cell response based on the previously reported performance of neoantigen-directed treatment approaches across tumor types, including melanoma, pancreatic cancer, and glioblastoma. However, Braun explained that neoantigen-targeting treatment presents a heightened challenge in kidney cancer, which, although immunogenic, has a modest mutation burden and therefore a lower number of targetable neoantigens. Nevertheless, acknowledging the dearth of effective RCC therapies in the adjuvant setting, Braun and colleagues aimed to design a personalized vaccine that could target the neoantigens present in kidney cancer.

Defining the Ideal Patient Population

This small study enrolled 9 patients with high-risk, resectable (stage III or IV) ccRCC who had undergone complete tumor resection.^1,2 The investigators created personalized vaccines for these patients through tumor sequencing and neoantigen prediction. These vaccines were composed of synthetic long peptides that contained up to 20 personal neoantigens present in each tumor. These peptides were divided into 4 pools to decrease competition with local lymph nodes in the event of certain epitopes presenting as immunodominant, Braun stated in a question-and-answer session following his presentation.¹

Regarding the later-stage patient population, when asked how neoantigen-directed vaccines might perform in earlier-stage tumors, Braun explained, “The immune composition is different in those early-stage tumors, so I don’t think we’ll know until we try. At the same time, some of those earlier-stage tumors tend to have excellent outcomes, so it’s not that [these vaccines] would be for every early-stage tumor, but if we can identify ones that are higher risk, those will be the ones to think about how to target.”

In another answer, he noted that the most convincing levels of success with cancer vaccines have been shown in settings of MRD, such as the adjuvant setting in kidney cancer. Therefore, he expressed that although the vaccines currently in development may not be advanced enough to elicit meaningful responses in the metastatic setting—at least when used alone—he and co-investigators hypothesized that this type of therapy would be most effective in patients with minimal, manageable disease that is nevertheless at high risk of recurrence.

Outlining the Trial Design and Feasibility Analysis

The vaccines were administered with or without ipilimumab (Yervoy) in 2 phases: a priming phase to activate and prime the T cells, followed by a boost phase to facilitate long-lasting T-cell memory.^1,2

Regarding the feasibility of manufacturing a neoantigen-directed vaccine for a disease with a low mutational burden, the investigators found that despite the low prevalence of coding mutations in the patient population, they could create a multi-epitope vaccine directed at single nucleotide variants and frameshift insertion deletions that corresponded with kidney cancer driver mutations.

Highlighting the Durable Efficacy of Personalized RCC Vaccines

From there, Braun explained that the second goal of the study was to determine the immunological efficacy of these vaccines.¹

“The basic question was: Are the T cells reacting to these neoantigens and capable of recognition?” He asked.

Prior to vaccination, most patients had barely detectable or undetectable levels of neoantigen immunity.^1,2 However, after vaccination, neoantigen-specific responses were observed in the peripheral T cells of all treated patients. For instance, at baseline, one patient had no detectable immunity for 3 of the 4 vaccine peptide pools. However, during the vaccination period, this patient exhibited strong peripheral T-cell responses.

When analyzing which neoantigens were associated with responses, Braun reported that, surprisingly, these results were not random. Instead, the investigators saw the most effective immune responses against known kidney cancer driver mutations, such as those in PIK3CA, PBRM1, KDM5C, BAP1, and VHL.

To determine the durability of these responses, the investigators tracked levels of vaccine-specific T-cell clones in the peripheral blood. At baseline, these levels were undetectable or near the lower limit of detection. However, upon vaccination, these levels rose rapidly, persisting through the boost phase. Additionally, Braun spotlighted that in some patients, vaccine-reactive T-cell clones were still observed months to years after vaccination, indicating the durable T-cell immunity elicited by this treatment.

Furthermore, the investigators conducted an in vitro assessment of the antitumor activity of these vaccines by placing vaccine-expanded T cells back on top of the corresponding patients’ tumors. In total, 7 of the 9 patients had generated detectable levels of vaccine-specific T cells that reacted against the autologous whole-tumor cells.

Overall, at a median follow-up of 40.2 months from the time of surgery, none of the enrolled patients had a recurrence of RCC.² Moreover, no dose-limiting toxicities were reported.

“We’re encouraged by the fact that all 9 patients, despite having high-risk disease, remained free of kidney cancer throughout the study,” he emphasized, noting that 1 patient died of unrelated causes during the study.^1,2

Acknowledging How the Study’s Limitations Give Way to Further Research

Braun noted that the small sample size is a key limitation of this research that warrants follow-up studies to determine the clinical relevance of these findings.¹

“These neoantigen vaccines are feasible for kidney cancer,” Braun concluded. “They can elicit effective T-cell responses and antitumor activity. At least this preliminary signal of clinical activity sets up [the phase 2] INterpath-004 [trial (NCT06307431)], the next study that will hopefully demonstrate some clinical activity.”

Notably, the phase 2 INterpath-004 trial (NCT06307431) is investigating adjuvant treatment with the mRNA-based personalized cancer vaccine intismeran autogene (V940) plus pembrolizumab (Keytruda) vs placebo plus pembrolizumab in patients with RCC.³

References

1. Braun DA. Personalized vaccines in kidney cancer: a journey from concept to clinic. Presented at: 2025 Kidney Cancer Research Summit; July 17-18, 2025. Boston, Massachusetts.
2. Braun DA, Moranzoni G, Chea V, et al. A neoantigen vaccine generates antitumour immunity in renal cell carcinoma. Nature. 2025;639(8054):474-482. doi:10.1038/s41586-024-08507-5
3. A study of adjuvant intismeran autogene (V940) and pembrolizumab in renal cell carcinoma (V940-004). (INTerpath-004). ClinicalTrials.gov. Updated May 13, 2025. Accessed July 17, 2025. https://clinicaltrials.gov/study/NCT06307431