No RCC Recurrence in Patients Treated With Adjuvant Neoantigen Vaccine

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A personalized cancer vaccine (PCV) demonstrated antitumor immunity and delayed recurrence in patients with advanced high-risk, fully resected clear cell renal cell carcinoma (RCC), according to results of a study from the Dana-Farber Cancer Institute and Broad Institute of MIT and Harvard published in Nature.¹

In the investigator-initiated phase I trial (NCT02950766), researchers found that at median follow-up of 40.2 months after surgery, none of the 9 participants had disease recurrence and no dose-limiting toxicities were observed. They observed T cell immune responses against the vaccine’s antigens, including those linked to common RCC driver mutations in VHL, PBRM1, BAP1, KDM5C and PIK3CA in all patients.

“The neoantigens targeted by this vaccine help steer immune responses towards cancer cells, with the goal to improve on-target efficacy and reduce off-target immune toxicity,” said co-senior author and co-principal investigator Toni Choueiri, MD, director of the Lank Center for Genitourinary Cancer at Dana-Farber Cancer Institute, in a press release.²

Neoantigens derived from tumor-specific mutations have been shown to be targets of T-cell mediated antitumor immunity and can be targets of PCV used in combination with immune checkpoint inhibitors such as in the KEYNOTE-942 trial (NCT03897881) in melanoma. Using PCVs has proved more challenging in diseases such as RCC with lower mutational burden and fewer potential neoantigen targets for PCVs, the investigators stated in their report.¹

The primary end points of the study were safety and tolerability and the maximum tolerated dose of locally delivered ipilimumab (Yervoy). Secondary end points included the induction of neoantigen-specific cellular immune responses following vaccination and the proportion of patients alive without recurrence at 2 years after resection.

Out of the 9 patients enrolled in this trial, 7 had high-grade disease and 2 had stage IV disease at baseline; 2 had ECOG performance status of 1 with the rest having performance status of 0. The size of their primary tumor before resection was between 4 and 7 cm in 4 patients, between 7 and 10 cm in 3 patients, and greater than 10 cm in 2 patients. Their tumors had a median of 45 high-quality coding mutations per sample.

All patients’ PCV included at least 1 peptide that resulted from a frameshift insertion and deletion that led to novel open reading frames, and 7 of 9 were vaccinated with a peptide that contained a neoantigen derived from a cancer driver mutation such as VHL, PBRM1, BAP1, KDM5C, and PIK3CA. Peptides were combined into 1 of 4 pools containing up to 5 peptides.

Five patients also receiving ipilimumab administered subcutaneously at 2.5 mg adjacent to the vaccination site with the other 4 only receiving the PCV. Unlike previous neoantigen peptides that were given subcutaneously, this trial administered PCVs with half the dose intradermally and half subcutaneously in order to engage antigen-presenting cells in both the dermis and epidermis.

The PCVs were found to be immunogenic in all patients and demonstrated immune reactivity against a median of 7 neoantigen vaccine peptides (range, 1-14). There were not substantial differences seen in the kinetics or peak magnitude of the immune responses in patients who received subcutaneous ipilimumab vs those who did not. Additionally, 98.7% of T cell responses originated from CD4+ cells.

Six patients were vaccinated with 7 peptides for the common driver mutations VHL, PBRM1, BAP1, KDM5C and PIK3CA, and 6 of the 7 induced an immune response following in vitro stimulation. Eleven out of 17 pan-cancer driver mutations were immunogenic and 50 of 112 passenger mutations were immunogenic.

Investigators identified 98 vaccine-expanded T-cell clones and observed a substantial rate of expansion beginning within 3 weeks, with these clones persisting for up to 3 years, predominantly in CD4+ T cells. In 7 of 9 patients, at least 1 vaccine peptide pool generated antitumor reactivity.

The most common adverse events were low-grade injection-site reactions in 100% of patients and transient flu-like symptoms in 8 of 9 patients. There were no reported grade 3 or higher toxicities or dose-limiting toxicities. Other reported adverse events were fatigue, malaise, increased alanine aminotransferase, decreased white blood cell count, decreased neutrophil count, and dry skin.

The investigators stated that although ipilimumab did not substantially change the magnitude or phenotype of the peripheral immune response compared with the vaccine alone, it did appear to influence antigen-presenting cells at the injection site, and they suggested higher doses could have more favorable results.

“We observed a rapid, substantial, and durable expansion of new T cell clones related to the vaccine,” said Patrick Ott, MD, PhD, director of the Center for Cancer Vaccines at Dana-Farber, in a press release. “These results support the feasibility of creating a highly immunogenic personalized neoantigen vaccine in a lower mutation burden tumor and are encouraging, though larger scale studies will be required to fully understand the clinical efficacy of this approach.”²

The ongoing multicenter international randomized phase 2 study INTerpath-004 (NCT06307431) is comparing a PCV in combination with pembrolizumab (Keytruda) vs placebo plus pembrolizumab in the adjuvant RCC setting.

_References:

_{1. Braun DA, Moranzoni G, Chea V, et al. A neoantigen vaccine generates antitumour immunity in renal cell carcinoma. Nature. Published online February 5, 2025. doi:10.1038/s41586-024-08507-5}

_{2. Cancer vaccine shows promise for patients with stage III and IV kidney cancer. News release. Dana-Farber Cancer Institute. February 5, 2025. Accessed February 5, 2025. https://www.dana-farber.org/newsroom/news-releases/2025/cancer-vaccine-shows-promise-for-patients-with-stage-iii-and-iv-kidney-cancer}