Patients with stage III or IV clear cell renal cell carcinoma may have achieved a successful anticancer immune response following initiation of a novel personalized cancer vaccine, according to a recent study published by Braun et al in Nature.
Background
The standard treatment for stage III or IV clear cell renal cell carcinoma is surgical resection to remove the tumor—which is often followed by immunotherapy with pembrolizumab, an immune checkpoint inhibitor that induces an immune response and reduces the risk of the cancer recurrence. However, about 67% of patients can still experience cancer recurrence and have limited treatment options.
“Patients with stage III or IV [clear cell renal cell carcinoma] are at high risk of recurrence. The tools we have to lower that risk are not perfect, and we are relentlessly looking for more,” stated co–senior study author Toni Choueiri, MD, Director of the Lank Center for Genitourinary Cancer at Dana-Farber Cancer Institute.
Study Methods and Results
In the investigator-initiated phase I trial, researchers assigned nine patients with stage III or IV clear cell renal cell carcinoma to receive a personalized cancer vaccine following surgical resection of the tumor. Five of the patients also received ipilimumab with the vaccine.
The novel vaccine was designed to train the body’s immune system to recognize and eliminate any remaining tumor cells using the tumor tissue removed during surgery as a guide. The researchers extracted molecular features known as neoantigens from the tumor cells that differentiated them from normal cells. The neoantigens—tiny fragments of mutant proteins—exist in the cancer but not in any other cells in the body. The researchers then used predictive algorithms to determine which of these neoantigens to include in the vaccine based on their likelihood to induce an immune response. The vaccine was manufactured and administered to the patients in a series of initial doses followed by two boosters.
“This approach is truly distinct from vaccine attempts in [clear cell renal cell carcinoma]. We pick targets that are unique to the cancer and different from any normal part of the body, so the immune system can be effectively steered toward the cancer in a very specific way,” emphasized lead study author David A. Braun, MD, PhD, a medical oncologist and physician-scientist at the Yale Cancer Center and Yale School of Medicine. “We learned which specific targets in the cancer are most susceptible to immune attack and demonstrated that this approach can generate long-lasting immune responses, directing the immune system to recognize cancer. We believe this work can form a foundation for the development of neoantigen vaccines in [clear cell renal cell carcinoma],” he indicated.
At a median of 34.7 months—the time of data cut-off—all of the patients remained cancer-free. Although some of the patients experienced local reactions at the vaccine injection site and influenza-like symptoms, no higher-grade adverse effects were reported.
“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,” Dr. Choueiri revealed.
The personalized vaccine approach had already demonstrated the potential to be effective in melanoma, which has more mutations and, therefore, many possible neoantigens. Because clear cell renal cell carcinoma is a disease with fewer mutations—and therefore fewer targets to manufacture the vaccine—it became critical for researchers to uncover insights about how the vaccine could influence an immune response to the tumor. Through a series of analyses, they found that the vaccine induced an immune response within 3 weeks, the number of vaccine-induced T cells increased by a mean of 166-fold, and these T cells remained in the body at high levels for up to 3 years. In vitro studies also showed that the vaccine-induced T cells were active against the patient’s own tumor cells.
Conclusions
“We’re very excited about these results, which show such a positive response in all nine patients with [clear cell renal cell carcinoma],” highlighted Dr. Choueiri.
“This study was the result of a close partnership between our NeoVax team, our colleagues at the Broad Institute of [the Massachusetts Institute of Technology] and Harvard, and our colleagues at the Lank Center for Genitourinary Cancer at Dana-Farber,” underlined co–senior study author Catherine Wu, MD, Chief of the Division of Stem Cell Transplantation and Cellular Therapies at Dana-Farber Cancer Institute and an institute member at the Broad Institute. “We are thrilled to report these results,” she added.
The researchers noted that larger clinical trials may be needed to confirm the effectiveness and explore the full potential of the novel personalized cancer vaccine. An ongoing, multicenter, international randomized study is currently examining the efficacy of a similar neoantigen-targeting personalized cancer vaccine in combination with immunotherapy pembrolizumab (ClinicalTrials.gov identifier NCT06307431).
“We observed a rapid, substantial, and durable expansion of new T-cell clones related to the vaccine,” underscored co–senior study author Patrick Ott, MD, PhD, Director of the Center for Cancer Vaccines at Dana-Farber Cancer Institute. “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,” he concluded.
Disclosure: The research in this study was funded by Gateway for Cancer Research, the U.S. Department of Defense, the Louis Goodman and Alfred Gilman Yale Scholar Fund, the Yale Cancer Center, Dana-Farber/Harvard Cancer Center, Harvard Medical School, the Trust Family Foundation, Michael Brigham, Pan-Mass Challenge, the Hinda L. and Arthur Marcus Foundation, The Loker Pinard Fund for Kidney Cancer Research at Dana-Farber Cancer Institute, the National Institutes of Health, and the Conquer Cancer Foundation/Sontag Foundation. For full disclosures of the study authors, visit nature.com.
