Personalized vaccine induces durable immune response in advanced kidney cancer
Key takeaways:
- All patients who received a personalized vaccine for advanced kidney cancer achieved an immune response.
- All patients remained disease free approximately 3 years after treatment.
A personalized vaccine demonstrated the potential to induce long-lasting immune response among people with advanced kidney cancer, according to results of a phase 1 trial.
All nine study participants — who had undergone surgery for stage III or stage IV clear cell renal cell carcinoma — remained cancer free approximately 3 years after treatment.
“These results are very encouraging, but we still have work to do to rigorously and systematically test the effectiveness of this approach in truly reducing the risk of cancer recurrence,” researcher David A. Braun, MD, PhD, assistant professor of medicine and Louis Goodman and Alfred Gilman Yale scholar at Yale School of Medicine, told Healio.
“Our goal was to generate an immune response against cancer-specific targets, effectively ‘steering’ the immune system to attack kidney cancer. Based on prior work, I had hoped that we were going to get some immune responses.
“Very encouragingly, we saw immune response in every patient,” he added. “The fact that we were nine out of nine, where all nine generated these good immune responses to the vaccine, was a bit surprising in a very positive way. The fact that the responses were so long lasting [and] that we still saw those vaccine-reactive T cells circulating in the blood was really encouraging, and probably exceeded expectations.”
Adding a ‘steering wheel’
Surgery is standard for people with advanced kidney cancer; however, those with stage III or stage IV disease remain at high risk for recurrence, Braun said.
For years, observation had been the standard approach after surgery. In 2021, the FDA approved pembrolizumab (Keytruda, Merck) as adjuvant therapy; however, only a third of patients respond.
“With anti-PD1 drugs like pembrolizumab, people often say, ‘There’s a brake that’s pressed on the immune system that’s preventing it from going. Let’s lift the brake.’ If the immune system is active, the hope is it can do its job, attack the cancer and clear any remaining cancer cells,’” Braun said. “But we know it doesn't do that for many patients. We’re not actually telling the immune system where to go. We’re taking our foot off the brakes, but we’re not actually steering it in any direction to say, ‘Go attack the cancer cells and don’t attack normal parts of the body.’ The question is: Can we add a steering wheel with a personalized cancer vaccine?”
Personalized cancer vaccines have shown promise in other malignancies.
One phase 2 study showed use of a vaccine with pembrolizumab conferred a 44% reduction in the relative risk for recurrence or death among patients with high-risk melanoma, according to study background. In a phase 1 trial, 50% of patients with pancreatic adenocarcinoma who received a personalized vaccine achieved an immune response.
“There are certain cancer types that have lots of mutations,” Braun said. “Melanoma has a huge number of mutations. Certain types of colon cancer do, also. In kidney cancer, the number is pretty modest. The question was whether we could actually do this for a modest mutation-burden tumor like kidney cancer.”
Methods
Researchers enrolled nine adults (median age, 65.5 years; range, 50.4-75.7; 78% men) with resected stage III or IV clear cell renal cell carcinoma.
Investigators evaluated the DNA and RNA of each tumor and developed personalized vaccines for each patient. They targeted a median 15 neoantigens (range, 8-19).
Vaccine development took approximately 12 weeks.
“We had about 12 weeks for the patient to recover from their surgery,” Braun said. “That’s the time we would let the patient recover from their surgery.”
Five patients received the vaccine with subcutaneous ipilimumab (Yervoy, Bristol Myers Squibb), an anti-CTLA-4 antibody, and four received only the vaccine.
Safety and tolerability served as the primary endpoint. Neoantigen-specific immune responses and DFS served as secondary endpoints.
Results
Median follow-up was 40.2 months after surgery and 34.7 months after vaccine administration.
At that time, all patients remained disease free. All achieved immune responses, and seven had T cells that reacted against their own tumors.
Braun characterized the vaccine as “very well tolerated.”
No trial participants experienced dose-limiting toxicities, and no grade 3 or higher adverse events occurred.
All patients developed injection site reactions (78% grade 1, 22% grade 2). Eight patients experienced flu-like symptoms for a few days, with six grade 1 cases and two grade 2 cases.
“This opens the door to the idea of tumor-specific vaccines for kidney cancer — not just in the adjuvant setting but potentially other settings, like the metastatic setting,” he added. “Could this be one of the co-therapies that we use together with conventional forms of immune therapy to not just activate the immune system, but also steer it in the right direction?”
Next steps
Braun highlighted the small sample size as a study limitation. He also emphasized the importance of not overstating the clinical impact of all nine patients staying disease free.
However, enrollment has begun on a phase 2 trial that is expected to include approximately 270 participants. Enrollment should likely conclude within the year, Braun said.
Researchers have partnered with Merck and Moderna on the study.
All patients will receive pembrolizumab, then half will get a vaccine and half will receive placebo.
“[This larger trial] will hopefully get us an answer on whether this is personalized cancer vaccine approach is more effective than pembrolizumab alone,” Braun said.
“I’m pretty excited,” he added. “Scientifically and immunologically, it’s doing what we were hoping for it to do. Now, we need to make sure that translates to doing something clinically. We need to do the testing. We need to be systematic. We need to be rigorous, but I am optimistic about those next steps.”
For more information:
David A. Braun, MD, PhD, can be reached at david.braun@yale.edu or on X (formerly Twitter) @BraunMDPhD.
Collapse