Hedy Tung

A team of Yale researchers recently published promising results from a clinical trial testing the effectiveness of a new cancer vaccine that treats patients with kidney cancer. 

The cancer vaccine provides a personalized treatment option for high-risk kidney cancer patients. The treatment centers around immunotherapy, a form of cancer therapy that focuses on getting the immune system to recognize and suppress the cancer. The team’s vaccine represents a recent shift to more targeted cancer therapies than general treatments like surgery, radiation and chemotherapy that tend to prolong life in advanced cancer patients but do not usually elicit long-term responses. 

“People have been trying to do [cancer treatment] for over 100 years at this point, but what was really the success of the last 15 to 20 years was that [scientists] realized that the immune system has certain brakes on it that can prevent it from doing its job,” David A. Braun, a professor and researcher, told the News. 

In a typical immune system response to a pathogen like the flu virus, the immune system recognizes the foreign invaders, attacks them and ramps back down once they have been cleared. However, the immune system does not typically recognize and attack cancer in the same way. Dr. Braun explained that cancer keeps the brakes on the immune system pressed, effectively hiding itself and preventing an immune response. 

Targeted immunotherapy

The current era of immunotherapies centers around the principle of taking off the brakes from the immune system to create an immune response to treat cancer. But, as Braun emphasized, simply activating the immune system is not enough to consistently target the cancer. 

“When you take your foot off the brake of the immune system, it’s actually not telling it where to go. It’s not telling it to attack the cancer. It’s turning on the immune system and hoping that that’s going to be the outcome,” Braun said. “And that’s been effective for some patients, but as we know, for so many patients, the current immunotherapies still are ineffective at either treating cancer, or preventing it from coming back.” 

While most vaccines today are preventative, the team’s cancer vaccine is therapeutic. According to Dr. Braun, rather than just taking off the brakes, the vaccine provides a steering wheel to guide the immune system to locate and attack the cancer. 

The vaccine is able to steer the immune system by targeting specific parts of the cancer unique to each patient. To find these discrepancies, the researchers performed DNA sequencing, RNA sequencing and a host of other tests on patients’ tumors. 

The research process

The trial included patients who had recently had their kidney tumors surgically removed, but who were at high risk for recurrence. The team created a personalized vaccine for each patient, with each vaccine taking three months to make on average. Braun mentioned that kidney tumor surgery patients typically need two to three months for recovery, so the timeframe for making the vaccine gave the team the perfect window to work on the vaccine. 

“I think if the question sometimes comes up, do you think that [timeframe] could be a lot shorter than three months? I think the answer is absolutely once this is done at a bigger scale and is automated in a way, I think that certainly that timeline is going to come down,” Braun said. 

The initial research began when Braun was working at the Dana-Farber Cancer Institute, and he noted that the cancer vaccine had interested him both clinically and scientifically. 

While drugs introduced in the last few years have helped treat high risk kidney cancer, there was no effective drug when Braun and his team began their research. 

“You would have a patient who just had surgery, with a third of a chance, or maybe even a 50-50 chance the cancer could come back. And there wasn’t anything you would do except just watch it,” Braun said. 

Braun added that despite new drugs for high risk cancer patients, clinic need is still very high for better treatment options. 

On the scientific side, Braun highlighted the importance of immunotherapy as a paradigm shift in cancer treatment. Historically, patients with advanced kidney cancer like metastatic or stage four kidney cancer live around a year from diagnosis to death. But, new immunotherapies show potential of extending patient lifespan by four to even nine years after diagnosis. 

While immunotherapy presents a promising way to treat cancer and have a significant long-term impact on patients, Braun acknowledged that there are limitations regarding the population that experiences its benefits. 

“Immunotherapy is this wonderful proof of concept that you have this tremendous control of cancer, but there’s a long way to go. It’s helping a certain number of people. That’s really important, but there’s many more people out there who are not right now getting benefit from it,” Braun said. 

Research planning and funding

The project required a great deal of coordination and team effort to ensure all the proper procedures were taken. This involved getting team members together and contracting a location for the genomic sequencing. The scientists designing the vaccine had to make it clinically appropriate, which required a great degree of specificity and planning by a great number of scientists, pharmacists and doctors to ensure its safety and efficacy. These were all important factors that the Braun team considered when designing the science. 

Braun worked with the patients in the clinical trial individually, analyzing their tumors to be able to fully understand their immune responses. 

The funding for this project came from the Gateway for Cancer Research, known for furthering innovative cancer research projects. The Department of Defense was also an important source of funding, as their research program helped fund a portion of the science involved in the study. 

The project had five major points of focus: feasibility, safety, evaluation of immune response, quality of the immune response and capability of the immune responses. The team had to evaluate if the project was feasible because it was something that had never been done before in kidney cancer patients. 

The researchers had to critically evaluate the trial to see if it is safe for humans. Then they evaluated if the vaccine would relieve an immune response, and thought about how they could utilize the immunotherapeutics in a way that would steer the immune system to attack cancer specific targets. The immune responses then had to be evaluated to see if they are lasting and capable of attacking the tumor directly. 

The trial also has its limitations, as this study in particular was only nine patients. To truly evaluate the efficacy of vaccines like this one, studies typically analyze data from hundreds or thousands of patients. However, in this trial, Braun and his team were looking more for an immune response and activity signal, rather than a definitive answer about the vaccine’s pharmaceutical efficacy. 

Effects of the vaccine

In the end, the team was able to manufacture a personalized vaccine for all the patients in the study, and no one experienced major side effects. Braun reported most patients presented with a little redness around the site of the injection and slight flu-like symptoms, including muscle aches and low grade temperatures. This was viewed as a positive sign by researchers because it indicated immune system activity. 

“The work was highly innovative. This type of personalized neoantigen vaccine approach has not previously been used in renal cell carcinoma,” Harriet Kluger, professor of medicine and dermatology, told the News. “Moreover, the scientific rigor in applying state of the art technologies to verify immunologic response to the vaccine is commendable.” 

The vaccine successfully generated an immune response, and researchers collected blood samples before, during and after the vaccine for some patients, up to months and years after they had finished the vaccine. They found that even years after they had the vaccine,patients still showed evidence of the vaccine-induced changes in their immune system, resulting in lasting immune memory against cancer targets. Researchers were able to collect the immune cells after vaccination and test them against the tumor to demonstrate the immune cells had become capable of recognizing the tumors. 

The researchers expected about one-third to one-half of the nine patients to have their kidney cancer come back, however none of those nine patients had their kidney cancer return. The first patient was treated in 2019, the next patient months after that and the rest staggered after that. 

Future research and expansion

Now, a larger, phase two trial is open in collaboration with larger companies like Merck and Moderna, which is now focused on studying the effectiveness of a personalized cancer vaccine in hundreds of patients. Yale remains a big part of that effort. 

“Dr. Braun and his team have produced a very important study. It shows that personalized vaccines are feasible, safe and potentially effective for Renal cell carcinoma. Further, Dr. Braun and his team showed that targeting driver mutations—the mutations that are most important in making cancer into cancer—is an effective vaccination strategy,” Jeffery Ishizuka, assistant professor of medical oncology, told the News. 

The phase two trial will continue to evaluate if the approach of a personalized cancer vaccine really works at a larger scale to decrease the chance of the kidney cancer coming back, but the longer term question focuses on how these cancer vaccines, particularly personalized vaccines, play a role in other types of cancers and other clinical settings. 

The Braun lab will continue to focus on these next generation of vaccine targets and explore their therapeutic potential in both clinical and scientific settings. 

“With continued development success, this approach and others like it could lead to a new standard of care in Renal cell carcinoma and save the lives of thousands of patients diagnosed with cancer,” Ishizuka said.

The Gateway for Cancer Research is located at 20 North Martingale Rd. in Schaumburg, Ill.