Image: Suzanne Camarata
After more than a century of hope and skepticism, cancer immunotherapy—harnessing the human immune system to beat back malignant tumors—has become a reality. Each year, more FDA-approved immunotherapies are saving and extending the lives of people whose cancers were previously considered untreatable.
Five scientists whose foundational discoveries led to these breakthrough clinical therapies were honored at the 2017 Warren Alpert Foundation Prize Symposium at Harvard Medical School.
The Oct. 5 symposium, “Immune Checkpoint Blockade and the Transformation of Cancer Therapy,” held in the Joseph B. Martin Conference Center with a standing-room-only crowd, featured talks by four of the five researchers who received this year’s prize.
“The pioneers we are honoring today have begun rewriting the history of cancer,” said George Q. Daley, dean of HMS. “While this may not be the final chapter in the story, it certainly is a pivotal twist in the plot.”
Long-awaited fruition
Symposium moderator Joan Brugge, the HMS Louise Foote Pfeiffer Professor of Cell Biology and director of the Ludwig Center at Harvard, introduced the keynote lectures by providing a crash course in the history of cancer immunotherapy.
She described how the story began in the 1700s, when people noticed that cancer patients with certain infectious diseases experienced tumor remissions. Then, in the 1890s, New York surgeon William Coley showed that about 10 percent of cancer patients could be cured by injecting them with Streptococcus bacteria.
Attempts to replicate Coley’s results faltered, however, and for most of the 20th century the medical establishment swung between optimism and doubt regarding the possibility of treating cancer by stimulating the immune system.
It was only in the last 30 years that scientists, most notably the five prize recipients, provided definitive proof that it could be done.
Under normal conditions, so-called checkpoint inhibitor molecules rein in the immune system to ensure that it doesn’t attack the body’s own cells. The collective work of the Warren Alpert Foundation Prize recipients demonstrates how tumors can hijack this self-defense mechanism to hide from the immune system.
The researchers identified specific proteins on the surfaces of T cells—immune cells that find and destroy invaders—and revealed how they drive normal T-cell function and subvert that function when tricked by tumor cells.
The scientists’ findings led to antibody-based therapies that modulate these proteins, CTLA-4 and PD-1, to free the hobbled T cells and make tumors vulnerable again to immune attack.
“I’ve been a bystander watching these ideas evolve over the last 40 years,” said Brugge. “The support and enthusiasm of the field waxed and waned, but some researchers persevered.”
A tale of two proteins
Prize recipient James Allison, professor of immunology and chair of the Department of Immunology at the University of Texas MD Anderson Cancer Center, shared his perspective on “where we are now and how we got here,” including an anecdote about his initial realization that manipulating CLTA-4 could theoretically treat any kind of cancer.
Blocking CTLA-4 in mice reactivated their T cells and destroyed tumors; they “became permanently immune,” he recalled. “I was stunned.”
“It took years to get people to believe us,” he added.
Eventually, others listened, and Allison’s research contributed to the development of ipilimumab, a drug that has improved metastatic melanoma outcomes from an average survival of 11 months to a cure rate of 22 percent.
Allison also summarized the differences between CTLA-4 and PD-1, including what they do at the molecular level, how fast they work and how likely it is that a patient’s cancer will recur after treatment.
Prize recipient Lieping Chen, United Technologies Corporation Professor in Cancer Research and professor of immunobiology, of medicine and of dermatology at Yale University, spoke about two main strategies in cancer immunotherapy: enhancing normal immune mechanisms and correcting defective ones.
Chen, who is also co-director of cancer immunology at the Yale Cancer Center, emphasized the need to better understand the biological microenvironments where patients’ tumors are located, even suggesting a new classification system for cancers based on microenvironment.
Stop and go
Prize recipient Gordon Freeman, professor of medicine at HMS and Dana-Farber Cancer Institute, then described the discovery of PD-L1 and PD-L2, molecules that bind to PD-1, suppressing T-cell activity and rendering tumors immune resistant.
He explained how tumors create a feedback loop that uses the immune response against itself: T cells recognize a tumor cell and produce interferon, which raises PD-L1 and turns off T-cell activity.
“As hard as you’re leaning on the gas, you’re stepping on the brakes,” he explained. “That’s why T-cell treatments hadn’t worked.”
Freeman said that cancer immunotherapies address such problems, which Chen calls adaptive immunity.
“If the tumor evolves and changes,” said Freeman, “the immune system can evolve and change.”
Prize recipient Arlene Sharpe, the George Fabyan Professor of Comparative Pathology and interim co-chair of the Department of Microbiology and Immunobiology at HMS, took a deep dive into the biology of the PD-1 pathway, including how it regulates memory T-cell function.
The fifth prize recipient, Tasuku Honjo, professor of immunology and genomic medicine at Kyoto University, was unable to attend the symposium.
From bench to bedside
Invited speaker and former HMS professor Michael Atkins, deputy director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, D.C., and professor of oncology and medicine at Georgetown University School of Medicine, provided a fitting conclusion by discussing how the prizewinners’ discoveries are making a difference in the clinic.
Today, an antibody therapy that targets CTLA-4 is FDA-approved to treat melanoma, and PD-1/PD-L1 therapies have been approved for the treatment of melanoma; kidney, lung, bladder, and head and neck cancers; some forms of colorectal cancer; Hodgkin lymphoma and Merkel cell carcinoma.
FDA approvals of checkpoint antibodies are “exploding,” said Allison, with 11 new drugs approved so far in 2017 and 1,300 clinical trials in progress.
“It’s a great time to be an oncologist or a researcher, because it’s a better time to be a patient,” said Freeman. “With this success, an amazing amount of human creativity has been unleashed. The best and brightest in science, the most adventurous in venture capital and pharma, are now focused on developing further immunotherapies.”
“Seeing the effects of PD-1 therapy changing the lives of patients is the biggest reward of all.”
—Arlene Sharpe
Multiple speakers remarked on how cancer immunotherapy emerged from basic research in laboratories that weren’t even focused on oncology.
“None of today’s speakers were cancer biologists. They all were working on fundamental issues of immunology,” said Brugge. “But their insights are what brought us here today.”
“The way we got here has nothing to do with understanding tumors,” agreed Allison.
“It’s really gratifying when basic science you do is translated,” said Sharpe. “For me, seeing the effects of PD-1 therapy changing the lives of patients is the biggest reward of all.”
Cancer immunotherapy demonstrates “how investing in basic science research can have an impact on human health,” Sharpe added.
The Warren Alpert Foundation Prize recognizes one or more scientists whose achievements have led to the prevention, cure or treatment of human diseases or disorders, or whose research constitutes a seminal scientific finding that holds great promise of ultimately changing our understanding of or our ability to treat disease. Nominations are open until Oct. 31 for the 2018 prize.
