‘The Next Wave’ in Cancer Vaccines

CURE, Immunotherapy Special Issue 2021,

Even with newer technologies such as mRNA, experts predict it will be a few years before another cancer vaccine is approved.

Earlier this year, BioNTech co-founder and chief medical officer Özlem Türeci stated that the messenger RNA (mRNA) technology used to develop two of the COVID-19 vaccines currently available in the United States could be used to treat another disease that affects millions of people around the world: cancer. The technology, which has been around since the 1990s but wasn’t widely used until now, carries instructions into the body to make proteins that prime it to attack a specific virus.

“The same principle can be applied to help a patient’s immune system to attack a tumor,” Dr. Julie Rosenberg, head of global clinical development at OncoPep, said in an interview with CURE®. The biotechnology company focuses on developing targeted immunotherapies and is currently focusing on PVX-410, an investigational cancer vaccine being studied in patients with multiple myeloma and triple-negative breast cancer.

The discussion of mRNA’s potential to be used in the cancer field comes more than a decade after the Food and Drug Administration approved the first cancer vaccine: Provenge (sipuleucel-T). In 2010, it was approved for the treatment of advanced prostate cancer. Provenge is composed of a patient’s own stimulated dendritic cells — a type of immune cell responsible for “educating” the immune system on what to target. During the process, the dendritic cells are exposed to prostate antigens. Provenge is known for its toxicity, and Rosenberg noted that newer, less toxic vaccines that are in development are being studied in clinical trials. Side effects of Provenge can vary, depending on the patient, but include chills, fatigue, fever, headache, muscle pain and loss of appetite. “It’s basically a cellular therapy where you take people’s cells out of their arm, you send them to a factory, teach the cells how to recognize prostate cancer and give them back to patients,” said Dr. Thomas Marron, director of the early phase trials unit at The Tisch Cancer Institute and assistant professor of medicine at Icahn School of Medicine at Mount Sinai in New York. Overall, the goal of a cancer vaccine is to teach the body how to recognize something foreign.

Marron added that cancer vaccines can also help a patient’s immune system learn what to be on the lookout for when it comes to their specific cancer. “One of the reasons why patients might not respond to the new immunotherapies used to treat many cancers is their immune system might not have been taught how to recognize the cancer from the get-go,” he said. “A patient’s T cells, which are really the soldier cells of your immune system, may not have been trained to recognize mutated protein acts.”

Since Provenge, there has been only one other approved cancer vaccine. Talimogene laherparepvec is used to treat melanoma that has recurred after surgery. “(An) effective cancer vaccine must target tumor antigens that may have low immunogenicity in the tumor environment or that may mutate to evade the immune response,” Rosenberg added.

Many Cancer Vaccines Under Investigation

There have been plenty of clinical trials that have assessed cancer vaccines. “It’s really not that the vaccines haven’t worked. They just haven’t worked well enough,” said Dr. George Peoples, the founder and CEO of Cancer Insight and professor of surgery at the Uniformed Services University in Bethesda, Maryland. Peoples leads research and testing in immunotherapy developed under the military’s Cancer Vaccine Development Program. Of note, there are no other vaccines on the brink of approval, but there are many under investigation.

Marron is one of the researchers behind some of these cancer vaccines, one of which he described as “super personalized.” In an interview with CURE®, Marron used the example of a patient with lung cancer to explain his trial that was presented at the American Association for Cancer Research (AACR) annual meeting. Even when a tumor is surgically removed, these specific patients have a 50% or higher chance of the cancer eventually coming back, according to Marron.

“Our goal with the personalized vaccine was to create what we call an adjuvant therapy, which is a therapy that you get after surgery to further decrease the likelihood of cancer coming back,” he said.

In Marron’s recently completed phase 1 study that was presented at the AACR annual meeting, 15 patients were enrolled to test the safety and efficacy of an adjuvant personalized neoantigen peptide vaccine.

It was this study that computer scientist Marc Baum found while researching prophylactic immunotherapy, otherwise known as preventive cancer treatment. He previously received a diagnosis of bladder cancer at 54, and had just been declared cancer-free. “I did it for myself,” Baum said. “I’m (also) a scientist, so I wanted to help out and give back to the future (patients with cancer).”

Marron’s trial successfully administered the vaccine to 87% of patients over the course of 27 weeks, and results showed that the vaccine was well tolerated, with only half of the patient population experiencing mild side effects. Data also found that there was T-cell growth, as well as reactivity to synthetic neoantigens (proteins that form on cancer cells and help the immune system respond to and attack cancer cells).

“Personalized (cancer) vaccines were new news out there, and I just got lucky that there was one that fit,” Baum explained. Of note, Baum is still cancer free.

There are several variables behind the rigorous process of getting a new cancer vaccine approved, but the largest lies within the disease, according to Peoples. For diseases such as COVID-19, the vaccine is designed to generate a response against a bacteria or virus, but for cancer, the disease starts within the body’s normal cells, which makes it harder for the immune system to recognize it. In turn, Peoples says, a cancer vaccine has to train the immune system to recognize and destroy unhealthy cells. “That’s a really big ask for the immune system,” he said. “(Because of this,) cancer vaccines have trailed far behind infectious disease vaccines.”

Over the past two or three decades, most of the research behind cancer vaccines was driven by the goal to figure out a way to identify potential targets on cancer cells so the immune system could be trained to recognize the difference. More recently, checkpoint inhibitors proved successful at this. Because they allow T cells to regain their ability to recognize and kill cancer cells, their use in combination with T-cell therapies has been a huge step in the right direction. “Their underlying benefit has really closed the loop, if you will, on some of our understanding on cancer vaccines,” Peoples said. He describes the combination as a “natural marriage,” since bringing the two together keeps the T cells from being turned off, so to say, by the tumor, leading to an immune response. “We now prove the immune system has the capacity to recognize and destroy cancer,” he explained, noting that there’s an outpouring of clinical trials to explore these different combinations.

Next Wave for Cancer Vaccines

In response to this research, Peoples mentioned that the focus will switch to how to best use those vaccines in terms of testing in the right patient population. “That’s really the next wave for cancer vaccines,” he said.

Peoples broke it down using the example of a patient with breast cancer who has a 30% to 40% risk of recurrence. He says the recurrence could occur over the next two to three years. “(For) a clinical trial to test a vaccine, where we’re trying to see if we can reduce a recurrence rate from 30% or 40% down to 10% or 20%, and we have to wait three years to find out if we’ve done anything ... that’s a very long, very expensive, very laborious trial,” he noted.

This serves as a huge obstacle in getting cancer vaccines approved — especially considering the already rigorous clinical trial process. “A comprehensive vaccine development process can take eight or more years to complete,” Rosenberg explained.

However, Peoples emphasized, the most important thing to remember is that there is information out there to create an effective cancer vaccine. “Additionally, there are some new vaccine technologies coming down that are extremely exciting, some of which will come from this pandemic,” he said. “(And) we’ll continue to look for those rationale combinations that will be required to be able to overcome disease burdens in patients with metastatic disease.”

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