Researchers at the Dana-Farber Cancer Institute report that all nine patients in a clinical trial treated for stage III or IV clear cell renal cell carcinoma (a form of kidney cancer) developed a successful immune response against cancer after receiving a personalized cancer vaccine. The vaccines were administered after surgery to remove the tumor and are designed to train the body's immune system to recognize and eliminate any remaining cancer cells. At the time of data cutoff (an average of 34.7 months), all patients were cancer-free.
The results of this phase 1 trial were published today in Nature.
The standard treatment for patients with clear cell kidney cancer in stage III or IV is surgery to remove the tumor. Surgery may be followed by immunotherapy with pembrolizumab, an immune checkpoint inhibitor. Pembrolizumab triggers an immune response that reduces the risk of cancer recurrence. However, about two-thirds of patients may still experience a relapse, and treatment options are limited.
"For patients with stage III or IV kidney cancer, there is a high risk of recurrence," says Choueiri. "The tools we have to reduce this risk are not perfect, and we are relentlessly searching for more."
In this investigator-initiated study, Choueiri and Braun treated nine patients with stage III or IV clear cell kidney cancer with a personalized cancer vaccine after surgery. Five patients also received ipilimumab in addition to the vaccine.
The vaccines are personalized to identify the patient's individual cancer using the tumor tissue removed during surgery as a guide. The team extracts molecular features from the tumor cells that distinguish them from normal cells. These features, called neoantigens, are tiny fragments of mutated proteins that are present in the cancer but not in any other cell in the body.
The team uses predictive algorithms to determine which of these neoantigens to include in the vaccine, based on their likelihood of triggering an immune response. The vaccine is then manufactured and administered to the patient in a series of initial doses, followed by two booster shots.
"This approach is very different from vaccine trials in kidney cancer," says Braun. "We are selecting targets that are unique to the cancer and distinct from any normal part of the body, so the immune system can be effectively 'directed' at the cancer in a very specific way. We have identified which specific targets in the cancer are most vulnerable to immune attack and shown that this approach can generate long-lasting immune responses that instruct the immune system to recognize cancer. We believe this work can form a foundation for the development of neoantigen vaccines against kidney cancer."
While some patients experienced local reactions at the vaccine injection site and others had flu-like symptoms, no more serious side effects were reported.
When the team began this study eight years ago, it was unclear whether this approach would work for kidney cancer. It had been shown that it might be effective for melanoma, which has many more mutations and thus many potential neoantigens.
However, kidney cancer is a disease with fewer mutations and therefore fewer targets for vaccine production. It was important for researchers to learn as much as possible about how the vaccine affects an immune response to the tumor from this early stage of the study.
Through a series of analyses, the team found that the vaccine triggered an immune response within three weeks, the number of vaccine-induced T cells increased 166-fold on average, and these T cells remained in the body in high concentrations for up to three years. In vitro studies also showed that the vaccine-induced T cells were active against the patient's own tumor cells.
"We observed a rapid, substantial, and durable expansion of new T-cell clones related to the vaccine," says Ott. "These findings support the feasibility of developing a highly immunogenic personalized neoantigen vaccine in a tumor with a lower mutational burden and are encouraging, although large-scale studies will be needed to fully understand the clinical efficacy of this approach."
To confirm the vaccine's efficacy and realize its full potential, clinical trials with a larger number of patients are needed. An ongoing multicenter, international randomized trial is administering a similar personalized neoantigen-targeted cancer vaccine in combination with the immunotherapy pembrolizumab (NCT06307431). Choueiri is co-chair of the scientific advisory board.
