Personalized Kidney Cancer Vaccines Show Early Promise

Immune Activation and Durable Responses Observed in High-Risk Patients

Novel personalized neoantigen vaccines have demonstrated early encouraging signs of activating the immune system and achieving lasting responses in select patients battling clear cell renal cell carcinoma (ccRCC). These findings underscore the need for further investigation into this innovative therapeutic avenue.

Targeting Kidney Cancer with Precision

At the 2025 Kidney Cancer Research Summit, **David A. Braun**, MD, PhD, detailed the design and rationale behind a phase 1 clinical trial that explored the effectiveness of custom-built neoantigen vaccines for individuals with high-risk, resectable ccRCC. The presentation highlighted the vaccines’ potential to combat tumors and suggested that the minimal residual disease (MRD) setting might be the most advantageous environment for developing such therapies for kidney cancer and other conditions with a lower mutational burden.

Dr. Braun, an assistant professor of medicine at Yale School of Medicine, explained that the fundamental aim of cancer treatments is to precisely and rapidly direct CD8-positive T cells toward the tumor. While past strategies involved releasing the “brakes” on the immune system with checkpoint inhibitors or engaging “gas pedals” with cytokines, the future lies in immune navigation. He likened personalized cancer vaccines to a sophisticated steering mechanism for the immune system.

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

Navigating the Challenge of Lower Mutation Burden

The potential of neoantigens as effective targets for T-cell responses has been observed in other cancers like melanoma and glioblastoma. However, kidney cancer presents a unique challenge due to its relatively modest mutation burden, resulting in fewer targetable neoantigens. Despite this, recognizing the limited treatment options in the adjuvant setting for RCC, Dr. Braun and his team developed a personalized vaccine designed to target the neoantigens present in kidney cancer.

Study Design and Patient Selection

The study involved nine patients diagnosed with high-risk, resectable ccRCC who had undergone complete tumor removal. Researchers engineered personalized vaccines for each participant by analyzing tumor DNA and predicting neoantigens. These vaccines consisted of synthetic long peptides containing up to 20 unique neoantigens found in each tumor. The peptides were administered in four separate groups to mitigate potential competition among epitopes in the lymph nodes.

When questioned about the application of neoantigen-directed vaccines in earlier-stage tumors, Dr. Braun commented that the immune microenvironment differs, requiring empirical testing. He also noted that while many early-stage tumors have favorable outcomes, identifying higher-risk early-stage cases for targeted therapy could be beneficial.

Dr. Braun further indicated that the most promising results for cancer vaccines have been observed in settings of minimal residual disease, such as the adjuvant treatment of kidney cancer. He hypothesized that current vaccines, while potentially insufficient alone for metastatic disease, would be most effective in patients with minimal but manageable disease that carries a significant risk of recurrence.

Feasibility and Immunological Response

The personalized vaccines were administered in a two-phase approach: an initial priming phase to stimulate T cells, followed by a boost phase to foster long-term immune memory. This regimen was given with or without ipilimumab (Yervoy).

Despite the low frequency of coding mutations in the patient group, researchers successfully manufactured a multi-epitope vaccine targeting single nucleotide variants and frameshift insertion deletions associated with kidney cancer driver mutations, demonstrating the feasibility of this approach for diseases with lower mutational burdens.

Durable Immunity and Antitumor Activity

A key objective was to assess the immunological effectiveness of the vaccines. “The basic question was: Are the T cells reacting to these neoantigens and capable of recognition?” Dr. Braun asked.

Prior to vaccination, most participants showed minimal or undetectable neoantigen immunity. Following vaccination, however, all patients exhibited neoantigen-specific responses in their peripheral T cells. One patient, who initially had no detectable immunity to three of the four vaccine peptide pools, developed strong peripheral T-cell responses during the vaccination period.

Interestingly, the most potent immune responses were directed against known kidney cancer driver mutations, including those in *PIK3CA*, *PBRM1*, *KDM5C*, *BAP1*, and *VHL*. These responses were not random, suggesting a targeted attack.

The persistence of vaccine-specific T-cell clones in peripheral blood was monitored to evaluate response durability. Levels, initially undetectable, rapidly increased post-vaccination and remained elevated through the boost phase. In several patients, these reactive T-cell clones were still detectable months to years later, indicating long-lasting T-cell immunity.

An in vitro analysis of the vaccines’ antitumor activity involved reintroducing vaccine-expanded T cells to the patients’ own tumors. Seven of the nine patients generated detectable levels of vaccine-specific T cells that reacted against their autologous tumor cells.

With a median follow-up of over 40 months post-surgery, none of the study participants experienced a recurrence of their RCC. 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,” Dr. Braun emphasized, noting that one patient passed away from unrelated causes during the trial.

Future Directions and Clinical Trials

Dr. Braun acknowledged the study’s small sample size as a primary limitation, stressing the need for larger studies to confirm the clinical significance of these findings. The feasibility of creating neoantigen vaccines for kidney cancer, their ability to elicit potent T-cell responses, and preliminary signals of clinical activity are paving the way for the next phase of research.

“These neoantigen vaccines are feasible for kidney cancer. 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,” Dr. Braun concluded.

The ongoing phase 2 INterpath-004 trial is currently evaluating the adjuvant treatment with the mRNA-based personalized cancer vaccine intismeran autogene (V940) in combination with pembrolizumab (Keytruda) compared to a placebo plus pembrolizumab in patients with RCC.