A Mountaineer Reaches for the ‘Everest’ of his Cancer Research Career

A T-lymphocyte (type of white blood cell) recognizes antigens on a cancer cell and binds to it. Therapeutic cancer vaccines can train the immune system to better recognize these tumor antigens.

By Sachi Fujimori, original article from Get Science.

New insights into the immune system are driving a recent resurgence in investigating vaccines that fight cancer tumors.

Avid mountain climber Bob Hollingsworth has scaled some of the tallest and most dangerous mountains in the world in his lifetime, from Mount Rainier in Washington to the Matterhorn in Switzerland.

Similarly, throughout his scientific career, Hollingsworth has been drawn to what he calls "The Everest" of medical fields: cancer.

"There's a part of me that really likes a challenge," says Hollingsworth, Vice President and Chief Scientific Officer for Cancer Vaccines and Immunotherapeutics at Pfizer's La Jolla, California research site. "When I tell colleagues in oncology that I'm a mountain climber, it's natural to them. We're drawn to really hard, complex challenges."

After decades of setbacks, Hollingsworth is optimistic about a new "summit" in his field of cancer vaccines, a type of therapy that aims to prime the immune system to attack tumors. Breakthroughs in this area have arrived thanks to years of research to better understand the genetics of cancer cells and how they interact with the immune system.

"The excitement comes from putting together pieces of knowledge that previously had not been synthesized to be able to achieve something new," says Hollingsworth. "It's also exciting because of the potential efficacy — that we might be able to get a lasting response and treat patients we otherwise couldn't treat before."

Known as therapeutic cancer vaccines, this class of treatments differs from conventional preventative vaccines in that they're given to a patient to treat an existing disease — in this case cancer. A separate category of cancer vaccines, which includes the human papillomavirus (HPV) vaccine, prevents cancer in healthy people by targeting infectious agents that can lead to cancer.

Building Upon Basics

The fundamentals of vaccination are very similar, whether you're dealing with influenza or cancer. When you get a flu shot, for example, you may receive an inactivated, or killed, form of the virus that teaches your immune system to develop specific antibodies that recognize and respond to an antigen — a piece of protein — on an invading virus. With cancer vaccines, an antigen from cancer cells is injected into patients to train the immune system to recognize molecules on the outside of tumors.

And similar to traditional vaccination, which can sometimes give you lifelong immunity against certain pathogens, cancer vaccines offer the potential to have a "memory component," Hollingsworth says. "These therapeutic vaccines may be able to trigger a durable response, meaning that after having killed the cancer, if the cancer tries to come back, the immune system will be in place to activate and attack."

Recent versions of cancer vaccines have been approved to treat prostrate, bladder, and skin cancers, but researchers have had challenges developing treatments for other cancers that produce a powerful enough immune response.

But now thanks to three developments, they're turning a corner: First, they have a better understanding of how to choose an antigen from cancer cells that will spur a strong immune response. Second, they've developed therapies that can potentially thwart the defenses that cancer cells use to avoid destruction by the immune system — what Hollingsworth calls "inhibiting the inhibitors." And third, they have new technologies that offer more potent ways of vaccinating to fight cancer, such as using weakened viruses — that are less likely to make patients sick — as carriers for the antigens.

"It's really the combination of these three elements that is generating some excitement just in the last few years that we're turning the corner with cancer vaccines," he says.

Partners in Combatting Cancer

Used in combination with well-established immunotherapy treatments such as PD-1 inhibitors (that block cancer tumors' ability to suppress the immune system), these cancer vaccines are part of what is known as a "Vaccine-Based Immunotherapy Regimen." "It's not just a vaccine," says Hollingsworth. "It ends up being a combination of really two or three drugs."

Answers in the Antigens

Developing the appropriate antigen for these vaccines has had its share of challenges, because unlike bacterial or viral pathogens, which the immune system can easily recognize as foreign, cancer cells stem from our own healthy cells and are thus harder to identify as targets of attack.

Cancer cells have certain traits, however, that do make them stand out. They can vastly over-express certain proteins that aren't present on healthy cells. And they can create what are called "neoantigens," new proteins that arise from a mutation in the cancer cell. "We've found these are the best targets for cancer vaccines because they are brand new antigens that are not presented in any normal cells," Hollingsworth says.

Personalized Vaccines

While current therapeutic vaccines are tailored to general types of cancer such as melanoma or prostate cancers, Hollingsworth sees a future where there may be more personalized vaccines tailored to a patient's own cancer cells. By using DNA-sequencing technology, a vaccine could be developed for the specific protein mutations on a patient's cancer tumor. "It's not easily scalable, however, because it's totally customized," he says of the limitations to widespread use.

But for now, Hollingsworth says he is excited about the confluence of research that has led to therapeutic cancer vaccines reaching this investigational turning point. "Cancer vaccines have had a long history of failure," he says. "But because of these new understandings, we feel we're on the edge of success."