Summoning the Troops
to Attack Colon Cancer

In 1993, Dr. Waldman had an epiphany while attending a research conference in Europe. He was listening to a panel of scientists recount their failed attempts to develop a new treatment for blood cancers called immunotherapy. The therapy bolsters the body’s immune system to fight cancer. Researchers who pioneered the approach would go on to win the Nobel Prize in Physiology or Medicine in 2018. But in the early 90s, cancer immunotherapy was still in its infancy. For Dr. Waldman, the panelists’ struggles conjured up an idea.

“If you could do these kinds of things in blood cancers, why not in colorectal cancer?” Dr. Waldman wondered, “Because I have the perfect immunological target for that.”

Dr. Waldman’s “perfect target” is a molecule called GUCY2C (pronounced “goosy toosy”), a protein that’s best known for mediating traveler’s diarrhea. Bacteria in contaminated food or water make a toxin that attaches to GUCY2C, which prompts the intestine to secrete water and salt, triggering diarrhea. He was studying GUCY2C in the context of infectious disease when it dawned on him that he was using colon cancer cells to investigate the molecule. He soon pivoted to the field of cancer and found GUCY2C is expressed only in the intestines and shows up in nearly all colon cancers, including primary tumors and tumors that have spread to other parts of the body. On normal gut cells, the molecule safely hides from immune surveillance, but acts like a beacon for immune cells when displayed by cancers that span into the bloodstream. It was the perfect molecule to sic the immune system on.

The only problem was that Dr. Waldman, a professor in the departments of Pharmacology and Experimental Therapeutics and Biochemistry and Molecular Pharmacology at Jefferson, is not an immunologist.

New Blood

In a few years, however, a newly minted bachelor’s degree student with an intense interest in immunology – and vaccines in particular – joined his lab. Adam Snook, PhD, had known his entire life that he wanted to become a scientist. As an undergraduate, he had fallen in love with immunology after taking one class and immediately began wondering why scientists couldn’t use immunology to fight cancer. As a graduate student, he had found the project, and mentor, of a lifetime in Dr. Waldman’s lab.

“Our goal was to create a vaccine that goes out and finds cancer cells resistant to chemotherapy and kills them,” says Dr. Snook who is now an assistant professor in the department of Pharmacology and Experimental Therapeutics at Thomas Jefferson University. Both are researchers at the Sidney Kimmel Cancer Center – Jefferson Health. If the team could do this, the ultimate hope was to bring the therapy to patients in need of a better option via clinical trials.

Colon cancer is the second most deadly cancer in the US. It is likely more than 51,000 people will die from the disease in 2019. Non-Hispanic blacks are particularly vulnerable to the condition, which strikes men more than women and seniors more than young adults. However, recent studies show that this particular cancer is on the rise in younger patients. Although colorectal cancer rates have dropped by more than 4% in those over 65 years old, incident rates are up 3% among millennials.

Immunotherapy Trial and Error

The task to develop a colon cancer vaccine was monumental. “We were creating everything from scratch,” says Dr. Snook. The researchers needed to create a brand new vaccine, brand new animal models and brand new tests to determine whether the vaccine was working.

“It actually took four years for me to have the first definitive piece of data that showed the overall concept was valid,” recalls Dr. Snook. “I was terrible at doing anything else. My wife wanted to kill me.”

Dr. Snook originally made three different vaccines, but none of them produced the immune response he was looking for. Exasperated, he decided to immunize mice with all three vaccines at once.

“It was like black and white,” he recalls. “All of the tumors in the control mice grew huge, whereas all the vaccinated mice controlled their tumors. That was by far the first piece of data showing we were on the right track, that GUCY2C could be an immune target.”

After another few years of refining the vaccine, Dr. Snook went on to show in mice that GUCY2C is indeed a potential cancer vaccine target. It safely fires up the immune system to attack cancers without attacking healthy cells. The next step was to test the vaccine in people.

“Nobody had ever done GUCY2C immunotherapy in people,” says Dr. Snook. “We really didn’t know what to expect.”

Vaccine Victory

As the nurse injected the first patient with the vaccine in the crowded hospital room, the room fell quiet. It would be several years before the researchers would be able to unblind and examine the data and see that their trepidation was for nothing. The patient responded well to the colon cancer vaccine. “It was the outcome we all wished for,” recalls Dr. Waldman.

The vaccine induced an immune response against tumors in five of the 10 patients enrolled in the study, Dr. Snook and team reported April 23, 2019 in the Journal for ImmunoTherapy of Cancer. Importantly, none of the patients showed serious side effects from the vaccine.

The clinical trial revealed why some patients’ immune systems did not react to the vaccine. The vaccine is made from a virus that almost everyone has had. It’s called an adenovirus, and is in the same family of viruses that cause the common cold, pink eye, croup and pneumonia. That means most people have some immunity against the virus and their immune systems resist the virus that is part of the vaccine.

In the study, the researchers measured patients’ preexisting immunity to the virus and found those with low immunity to the virus responded to the vaccine, but those with high immunity did not.

Dr. Snook and colleagues are now working on a solution, a modified version of the virus that makes it less susceptible to a patient’s preexisting immunity. The researchers will begin another trial this fall with the new version of the vaccine.

“Developing effective strategies for treating solid tumors with immunotherapy— which has been successful in a subset of blood cancers—is a major focus for experts at the Sidney Kimmel Cancer Center. Drs Waldman and Snook exemplify the creativity that emerges from our interdisciplinary teams, and this is a major step forward toward the goal of designing new treatment paradigms for colorectal cancer,” says Karen Knudsen, PhD, Enterprise Director, NCI designated SKCC — Jefferson Health.

Beyond Colon Cancer

The team had thought GUCY2C was only present in colorectal cancers, but colleagues suggested they look at gastric and esophageal cancers as well since these cancers evolve from pre-cancerous cells that look like intestinal cells. Dr. Waldman was skeptical.

“I thought it was going to fail,” he says. “We needed to look because we didn’t want to miss anything, but the whole way I was thinking, ‘this is never going to work.’”

Although healthy esophagus and stomach cells do not make GUCY2C, the way colon cells do, Dr. Waldman and colleagues found when these cells begin to transform into precancerous intestinal-looking cells, they also began making GUCY2C. The same is true in some pancreatic cancers. Esophageal, gastric and pancreatic cancers are some of the most lethal cancers. About 25% of all cancer-related deaths in the US result from cancers that express GUCY2C.

“To find out you’ve discovered a target that is actionable in a disease that is almost uniformly fatal in patients is a eureka moment,” says Dr. Waldman. “If it pans out that these therapeutic approaches are effective, we could have profound impact on people who are desperate for an effective treatment.”

The researchers’ next trial will include the four cancer types – colorectal, esophageal, pancreatic and gastric cancers.

Dr. Waldman attributes much of the therapeutic potential to Dr. Snook. “He came in and was able to single-handedly put the idea into execution,” he says. “This work takes a lifetime and this is a multigenerational team sport. That’s why Dr. Snook is so important. He’s going to carry the torch forward long after I’m gone.”

Opener Photo Credit: Kevin Monko

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The Perfect Tag for CAR-T

When Drs. Waldman and Snook thought about how to use the GUCY2C antigen, they didn’t just create one kind of cancer vaccine. They also wondered whether it might be effective in a different immunotherapy approach that had taken the cancer-therapy world by storm.

It began with Emily Whitehead, who was only 7 years old when she was treated with a experimental cancer immunotherapy that would cure her leukemia. It was a risk, but one of the last options available to her and her family. She captured the attention of a nation and showed that immunotherapy was a real contender in the fight against cancer. Many patients soon followed in her footsteps.

The immunotherapy approach that cured Emily has the same goal but works very differently than vaccines and is developed for one patient only. The technique, now FDA approved and offered to patients with certain types of cancers, is called CAR-T, for chimeric antigen receptor T cells, and modifies a patient’s own immune cells with the ability to “see” a tumor antigen and fight the cancer attached to it.

But the success of CAR-T depends on identifying a tumor antigen – a specific tumor marker or ID tag – for that type of cancer. Because cancers are born out of normal healthy cells, researchers haven’t been able to find unique ID tags for all cancers.

So when Drs. Snook and Waldman started working with GUCY2C, they wondered whether an approach like CAR-T could work for colorectal cancer as well. They designed a CAR-T cell that recognized the GUCY2C tag and showed the approach was effective in killing tumors and preventing metastatic growth in mice.

While the researchers now focus on their adenovirus-based vaccine trial, they are also planning a GUCY2C CAR-T cell trial that will begin in 1-2 years.