Kidney Cancer Vaccine Shows Success in Small Trial

Might a kidney cancer vaccine that prevents recurrence change the trajectory for patients with the disease? It’s possible, based on a recently published Yale study. Though the study is small and early stage, the results are very promising.

The study involved nine patients with advanced kidney cancer. All nine had undergone surgery for an advanced form of clear cell renal cell carcinoma (the most common type of kidney cancer) and remained cancer-free for approximately three years and beyond after treatment with a personalized vaccine. Those results demonstrated a robust immune response in patients with stage III and IV cancer who were at a high risk for the cancer returning. These personalized vaccines were designed specifically to arm each person’s immune system to fight the specific cancer-causing genetic mutations found within their tumors.

While this finding was widely hailed as ground-breaking, given the patients’ robust, long-lasting immune response, it is only one example of the research that Yale Medicine oncologist David A. Braun, MD, PhD, principal investigator of the study and his lab colleagues are tenaciously pursuing. Their goal? Further discoveries and treatments that will enable an individual’s own immune system to attack, control, and eliminate cancer—an approach known as immunotherapy.

“I'm not particularly biased toward one immunotherapy approach,” he says. “I think vaccines have legs, but I think they are by no means the only approach we can use to re-direct the immune system to attack cancer.”

Because it is now widely understood that every cancer is as individual as the person who has it—meaning there is not one cure, but rather thousands—the newest treatments depend on continued deep research, including understanding the genetic makeup of the person with the disease.

We sat down with Dr. Braun to discuss his team’s notable findings and ongoing research.

It all starts with the patient. I see patients with kidney cancer in the clinic at Smilow Cancer Hospital. And I’m always trying to balance where we are now in their treatment with what I think is very real cause for optimism based on the ongoing research. I’m very truthful about what is available and what is in the research pipeline for cancer therapies.

With oncology, you really have a different connection with patients. You are with them during the highest highs and the lowest lows. You build relationships with patients and the families that last for years.

I always try to put myself in the patient’s place before I walk into the examination room. My own mother passed away from cancer when I was in graduate school, but she was diagnosed when I was in middle school, so we lived with it for some time. I remember being on the other side of the clinic room, and for me, this memory is centering—ultimately, everything we do has to be about the patients and their families.

Most cancer types are not ones where universal vaccines are possible. That’s because, with some potential exceptions, the cancers are too diverse. In general, therapeutic vaccines require a personalized approach. Even within a cancer type like kidney cancer, you could have 10 different patients who have cancer that looks exactly the same under the microscope. But if you looked more closely, at the genetic level, their mutations would be completely different. So, for most patients, and certainly for those with kidney cancer, it really has to be a personalized or bespoke approach.

It took us, on average, about 12 weeks per vaccine, in part because it was the first time we had done it, but also because this is an academic setting—and we really did want to learn. We wanted to be thoughtful because there’s actually a huge amount of nuance to these choices.

The process took time because we knew we were not going to be 100% correct in assessing the mutations and determining which would be a good immune target—or good antigen. The immune system tags foreign substances or pathogens in the body with an antigen, a nametag, that identifies it as a threat to be disarmed or destroyed. For each patient, we discussed each potential target that went into the vaccine.

It is likely to be two to three years, so by 2027 or 2028. It is a large-scale, randomized international trial involving approximately 270 patients at many large cancer centers, including Yale.

When we started with the first phase, there was no effective therapy, meaning for a patient who had surgery for high-risk kidney cancer, we knew that a third to half of the patients were at risk of it returning. There was nothing that could be done except to watch it. But since the first study, a common immunotherapy drug, Keytruda®, has become the standard of care. On the new phase II trial, every patient is treated with Keytruda, so half the people will get Keytruda with the vaccine, and other half will have Keytruda and a placebo.

Now we are waiting for everyone in the new trial to finish treatment, and obviously that will take some time—hopefully, a long time if the patients do not have their cancer come back—to actually see if the vaccine is truly protective. The timeline is decided by events [cancer recurrences]. We have to see a certain number of events to determine if there is separation in outcomes between those who got the vaccines and those who did not.

Our lab is a dedicated research group of immunologists and computational biologists. We’ve got lots of clinical trials going on right now that cover the disease spectrum and stages. We are using large-scale genomics [the study of a person’s entire set of genes, or genome] to understand how the tumor and genetic factors contribute to medicines working or not working, ultimately with a goal of matching the best drug to the best patient to receive that drug.

Also, we’re using some machine learning-based approaches to try to molecularly classify cancers into different types. Maybe different molecularly driven subtypes will respond differently to alternative immune therapies. We also use a lot of single-cell approaches, studying cancer at the level of individual cells and how they behave inside a tumor. [A relatively new approach, single-cell research is more detailed than an analysis of a crowded group of tumor cells.] We are looking at what are the parts of the tumor microenvironment itself that might lead to a response or not?

A tumor is not just cancer cells. It’s actually a really complex ecosystem. If you look under the microscope, it has dozens and dozens of different types of cells. We study that to learn what might lead the disease to progress from a curable early-stage disease all the way to a really devastating advanced disease. And what are the things that affect response or resistance to a therapy? So, we take one cell at a time and sequence it, not just a whole massive tumor, to understand what is in the composition of those different tumor types.

Early on, what was so transformative and paradigm-shifting about immune therapies was looking at the subset of traditionally treated patients who looked like they were—I’m hesitant to use the word ‘cured’—but were really having long-term control of their disease and living for years and years. In kidney cancer, it may be only 10% or 15% of people with advanced disease. However, this was proof of concept that the immune system can really—not just temporarily—control cancer.

With immune therapies, I take a big-picture view. I think about how can we improve on that 10% to 15% long-term disease control rate, and study all of the levers we can pull in the immune system to try to improve that percentage. I’m enthralled by the idea of using the immune system to control cancer.

As research is helping us to fine-tune immune therapies, they have joined the other pillars of cancer treatment: surgery, radiation, and chemotherapy.

The first generation of immunotherapies thwarted cancer’s ability to block the immune system’s guardians, T cells that attack and eliminate disease. These therapies, effectively, took cancer’s ‘foot off the brake,’ allowing disease-fighting T cells to drive toward removing cancer cells.

But there are many other levers than the ones that have been utilized so far in the clinic. There are gas pedals too, just like in cars, that you can really push on and make the immune system go faster. With either of those approaches, the therapy makes the immune system drive faster, the car goes faster but the therapies, so far, do not actually tell it [the immune system] where to go.

What we’re exploring is the idea that you can really steer the immune system in an extremely specific way toward the cancer cells…not just activate it, but actually tell it where to go.

Learn more about Yale Cancer Center clinical trials.

Research reported in the cancer vaccine study was supported by the National Institutes of Health under award numbers 1R37CA279822-01 and P30CA016359. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. The research was also funded by the Gateway for Cancer Research, U.S. Department of Defense, Louis Goodman and Alfred Gilman Yale Scholar Fund, Yale University, Dana-Farber/Harvard Cancer Center, Harvard Medical School, Trust Family Foundation, Michael Brigham, Pan Mass Challenge, Hinda L. and Arthur Marcus Foundation, The Loker Pinard Fund for Kidney Cancer Research at Dana-Farber Cancer Institute, and Conquer Cancer Foundation/Sontag Foundation.