Searching for a Universal Cancer Immunotherapy

By Deborah Balthazar | Illustrations by Grace Russell

It was the spring of 2018 at Thomas Jefferson University’s commencement ceremony, and Adam Snook, PhD, and Mỹ Mahoney, PhD, had never met before. They worked in two different departments on very different research projects. Dressed in their academic regalia, they shuffled inside to find their seats. Before the ceremony began, Dr. Snook, a cancer immunotherapy researcher, glanced at the name tag on the seat next to him and quickly looked it up on his phone.

“When I walked up to my seat, I saw this man on his phone,” recalls Dr. Mahoney, a biomedical researcher who studies skin biology. “The next thing I knew, he leaned over and said, ‘Hey, you want to work on CAR-T together?’”

This serendipitous exchange led to the start of a groundbreaking research project. Together, Drs. Snook and Mahoney have set out to work on a new version of CAR-T, one of the biggest advances in cancer immunotherapy. Their goal is ambitious: to potentially solve two of CAR-T therapy’s biggest challenges. First, expanding CAR-T to treat a wide range of solid tumors for cancers like breast, colon, pancreatic, lung, prostate and liver, which the therapy currently doesn’t effectively target. And second, making CAR-T accessible for more patients. The therapy’s current mode of production requires a lot of time and money, and there’s a limit to the number of people who can be treated with these potentially curative therapies.

By the time their students were crossing the stage, accepting their diplomas, Drs. Snook and Mahoney had already started charting their next steps.

Immunotherapy– A Revolution in Cancer Treatment

For over 160 years, scientists have searched for ways to harness the body’s immune system to fight cancer. Early efforts, dating back to the 19th century, explored whether infections could stimulate the immune system to attack tumors. By the 1960s, researchers had identified key immune system components, like T cells, that played an important role in recognizing and eliminating early cancers. The first breakthrough in this line of research came in the 1980s, when researchers discovered that T cells could be genetically modified to recognize and destroy cancer. This led to the development of chimeric antigen receptor T-cell therapy, or CAR-T.

The therapy is made by removing T cells from the cancer patient, turning them into stronger cancer-fighting cells in a laboratory, and then restoring them to the patient. The first-generation CAR-T cells, developed in the 1990s, showed promise in the lab and in mice, but failed in human trials. The modified T cells struggled to persist in the body, and there was no reduction in tumor size. At the same time, other forms of immunotherapy — such as cancer vaccines and immune checkpoint therapies — were being explored as alternative strategies, but they each had their own hurdles.

In 2001, Dr. Snook had started his PhD research in the midst of these exciting times in immunotherapy. His early work focused on developing cancer vaccines, but by 2009, his focus expanded to include CAR-T therapy just as the field was experiencing a turning point. Researchers had developed a new generation of CAR-T cells, improving their ability to persist and attack cancer cells.

This led to the landmark FDA approvals of six CAR-T therapies between 2017-2022, which were made possible by years of clinical trials, and early high-profile successes, including the first successful use of CAR-T therapy in a pediatric patient in 2012.

But while it has been revolutionary for some cancers, CAR-T therapy has significant limitations. One is that it is highly personalized — each patient’s own immune cells must be collected, modified to recognize and target the patient’s specific cancer type and then infused back into the patient. Essentially, no two patients would ever receive the same therapy. For that reason, the process of making the therapy is both time-consuming and expensive, costing hundreds of thousands of dollars per patient. 

“The current capacity is just a few thousand patients who can be treated annually,” says Dr. Snook. Because the therapy is generated for one patient at a time, there is a massive bottleneck on the number of patients that CAR-T can be manufactured for each year. “And so, we need to be able to do something different that could be applied more universally,” he continues.

Dr. Snook and Dr. Mahoney, associate professor and professor, respectively, in the department of Pharmacology, Physiology, & Cancer Biology, began to discuss more of a “one donor, many recipients” model. “It’s a challenging proposition, but it’s the only way to be able to scale CAR-T cells to treat many, many people in a single year,” says Dr. Snook.

Taking a universal approach would also allow for an expansion of the types of cancer for which CAR-T therapy can be used. But that raises a critical question: How do you take a one-person therapy and make it work for thousands without losing its incredible effectiveness? This is where the target protein underlying Dr. Mahoney’s research provided a potential solution.

From Dermatology to Cancer Therapy: The Role of DSG2

The ideal target is one that answers one of the stickiest problems in immunotherapy: finding molecules that are unique to cancer cells and not found in normal cells. That way, the CAR-T therapy would not attack normal cells in an autoimmune reaction. Dr. Mahoney’s almost three-decades-long research on a family of proteins called desmosomes has shown that they have unique properties that make them very promising as a candidate for a semi-universal target.

Desmosomal proteins help hold skin cells tightly together and control growth. When Dr. Mahoney started to study the role of these proteins in autoimmune diseases of the skin, she came across a lesser-known type of desmosomal protein called desmoglein 2 (DSG2). It was largely overlooked, most likely because it was expressed in such low levels in the skin.

Normally, DSG2 levels drop in adulthood and become essentially hidden from immune cells. But in many epithelial-derived cancers — like breast, colon, pancreatic, lung, prostate and liver — the DSG2 levels persist, making them a strong target for a wide array of cancer types.

Putting DesmoCART to the Test

Feeling confident that this idea would work, Drs. Snook and Mahoney started writing grants and creating CAR-T cells right away. To cover all bases, they designed tests to see if the therapy worked against cancer cells, while preventing the autoimmune toxicity that can happen when CAR-Ts attack normal cells.

In one experiment, the researchers injected mice with colorectal cancer cells under their skin. When they were given DesmoCART cells, the researchers observed that tumors disappeared after 28 days and they stayed in remission for at least four months after the experiment.

Testing for efficacy is relatively easy, but testing for safety is a different story altogether. “Safety is not commonly tested at this stage. A big reason is that it’s hard,” says Dr. Snook. Because there is no perfect way to replicate what would happen in a human body with model systems in the lab like mice and cancer cells, Drs. Snook and Mahoney tried as many systems as they could to come close to replicating human biology.

In general, CAR-T molecules are very specific — for example, they will not bind to other DSG proteins, like DSG1 or 3 or 4. But they also don’t usually cross species lines either, meaning that they couldn’t use a regular mouse model to test the therapy. They had to create a transgenic mouse that had both human cancer and expressed human DSG2 proteins on its normal cells.

When they gave the DesmoCART cells to those transgenic mice, the researchers found no obvious signs of toxicity: significant changes in body weight, signs of organ damage or diseased tissue, compared to control CAR-T cells. The lack of toxicity is promising because this might mean that cancer cells would be destroyed while healthy cells are left alone.

Another part of that experiment was to look at whether the DesmoCART cells could keep fighting cancer if it came back after the initial treatment. The researchers challenged mice with a second dose of cancer cells after the DesmoCART had successfully fought off the first dose. “We showed there was immune memory,” Dr. Snook says. The mice’s immune system remembered the cancer and the DesmoCART cells were still there to fight those cells off. “And that’s really important! From a patient’s perspective, it’s crucial to make sure that the T cells can attack a recurrent cancer.”

The Road Ahead

Now, with promising results in hand, Drs. Snook and Mahoney believe that they have enough preclinical data to get an investigational new drug certification from the FDA to start a clinical trial.

“Raising the money is really the biggest hurdle,” says Dr. Snook. “It’s probably at least $10 million to get from where we are today to do a trial.”

The uphill battle might be a little easier now that Dr. Snook agreed to license the DesmoCART therapy to the life sciences company Vittoria Biotherapeutics.