The 'Family Business' Behind the Flurry of PD-1 Inhibitors

Alexander M. Castellino, PhD

September 10, 2014

Three years after the much-heralded launch of ipilimumab (Yervoy, Bristol-Myers Squibb), cancer immunotherapy has new stars. At this time, they are most prominently the programmed death (PD) 1 inhibitors pembrolizumab (Keytruda, Merck & Co) and nivolumab (Bristol-Myers Squibb). But more of these agents, which include MPDL3280A (Genentech) and MEDI4736 (MedImmune/AstraZeneca), are under study and have demonstrated notable early results. The superabundance of activity within 1 class of drugs has likely prompted many observers to wonder: How did all of this come to pass?

The backstory of the development of PD-1 inhibitors involves many scientists whose discoveries have unveiled how the PD-1 pathway inhibits immune responses and cancer cells hijack PD-1 to prevent the immune system from recognizing and eliminating them.

But the story of how so many companies have come into possession of these secrets is a special part of the narrative and involves a pair of scientists from Boston who have contributed much to understanding PD inhibition.

Meet the husband-and-wife team of Gordon Freeman, PhD, associate professor of medicine, Department of Medical Oncology at the Dana-Farber Cancer Institute, and Arlene Sharpe, MD, PhD, the George Fabyan Professor of Comparative Pathology in the Department of Microbiology and Immunobiology at the Harvard Medical School, Boston, Massachusetts, who have been critical in assembling pieces of this immunotherapy puzzle.

"I joke that it's the family business," Dr. Freeman told Medscape Medical News about their shared research focus.

Dr. Gordon Freeman

Discoveries from the couple's respective labs have translated into therapies that are changing the face of cancer treatment — a process that spanned approximately 15 years. Drs. Sharpe and Freeman hold several patents on the PD-1 pathway and immune checkpoint inhibitors.

A key business decision from their affiliated Office of Research and Technology Ventures helped spread their discoveries to an array of drug developers.

The business decision was recently explained by a colleague at Harvard, oncologist Keith Flaherty, MD, in a Harvard press statement.

"Harvard and Dana-Farber nonexclusively licensed the intellectual property so all these efforts could multiply. It unleashed a bunch of therapeutic scientists on the problem so people could start engineering different antibodies. Some have worked and some have not, so this [nonexclusive licensing of PD-1-related intellectual property] is a real blessing."

The nonexclusive licensing to 7 pharmaceutical companies — Bristol-Myers Squibb, Merck, Genentech, Novartis, Boehringer Ingelheim, Amplimmune/AstraZeneca, and EMD Serono — has led to a flurry of PD-1 inhibitors that are being tested in clinical trials.

According to Dr. Freeman, "Work on PD-1 was a watershed moment for pharmaceutical development."

Dr. Arlene Sharpe

He explained that the PD-1 pathway started as a basic lab discovery and has now really taken off. "We've cured cancer 50 ways in mice, but PD-1 is what works well in people," he added.

Drug development on the first PD-1 inhibitor, nivolumab, was accomplished by Alan Korman's team at Medarex, a biotech company with research facilities in California that was acquired by Bristol-Myers Squibb in 2009.

The PD-1 inhibitors seem to reverse tumor escape from immune surveillance across several cancers, including melanoma; lung, bladder, and kidney cancers; and Hodgkin lymphoma. These cancers are being targeted with PD-1 inhibitors used alone or in combination with other inhibitors that target specific pathways associated with tumor proliferation.

On September 4 the US Food and Drug Administration approved Merck's drug pembrolizumab for the treatment of patients with advanced melanoma. Moreover, nivolumab, another PD-1 inhibitor, from Bristol-Myers Squibb and Ono Pharmaceutical, was first approved in Japan last month.

However, the patent wars are already on. Recent reports indicate that Bristol-Myers Squibb, makers of nivolumab, is suing Merck, makers of pembrolizumab, in the US District Court of Delaware, for patent infringement.

Assembling the PD-1 Puzzle

Any telling of the story of the development of PD inhibitors should mention Japan. That's where Tasuku Honjo, MD, PhD, from Kyoto University School of Medicine, and his colleagues first identified the PD-1 molecule in the 1990s.

However PD-1's physiologic function remained elusive for many years. The first glimpse that it was involved in negatively regulating the immune response, which exquisitely recognizes self from nonself and destroys nonself, came from experiments showing that autoimmune-prone mice lacking PD-1 developed lupus-like syndrome.

But for Dr. Freeman, the PD story precedes the 1990s and goes back to 1987, when a molecule called B7 — the seventh antigen on B cells — was discovered. B7 belongs to a family of ligands that activate T cells in major ways. With the completion of the Human Genome Project, Dr. Freeman and his colleagues looked into the database for other sequences that were similar to B7 sequences. In PD-L1 and PD-L2 — "cousins of B7" — they discovered ligands that bind PD-1.

In a collaboration, which included Clive R. Wood, PhD, then at the Genetics Institute and Wyeth Research, and Japan's Dr. Honjo, Dr. Freeman showed that the PD-1/PD-L1 interaction resulted in "negative regulation of lymphocyte activation." It turns off the immune response and provides a drug target, Dr. Freeman said.

Simultaneously, PD-L1 was independently discovered by Lieping Chen, MD, PhD, then of Mayo Clinic in Rochester, Minnesota, and now at Yale University in New Haven, Connecticut, who also offered insights into its significance.

In Dr. Sharpe's lab across the Harvard campus, other pieces of the puzzle were being assembled. "Early on PD-L1 was intriguing because we wanted to understand what differentiates it from B7," she told Medscape Medical News. With the discovery that PD-L1 was present on hematologic and other cells, it soon became apparent that it provided inhibitory cues in tissues, she said.

In a collaboration with Rafi Ahmed, PhD, at the Emory University School of Medicine, Drs. Sharpe and Freeman and their colleagues showed that PD-1 belongs to a family of molecules, which includes CTLA4 (the target for ipilimumab), that are continually upregulated on dysfunctional T cells.

In a mouse model of chronic infection, they showed that upregulation of PD-1 was associated with an unrelenting stimulation of T cells, leading to "T-cell exhaustion." Blocking PD-1 or PD-L1 using antibodies developed in Dr. Freeman's lab had a dramatic effect: The T cells revived and assumed their normal role.

Thus, PD-1 was identified as a mediator of T cell exhaustion in chronic infection. A similar situation occurs in tumors, she told Medscape Medical News.

The excitement mounted when the husband-and-wife duo discovered PD-L1 was overexpressed on tumor cells. In so doing, tumor cells had learned how to hijack the PD-1 receptor on T cells, which infiltrate tumors. The PD-1/PD-L1 interaction in the tumor microenvironment turns off the immune response so crucial to tumor recognition and elimination.

For their pioneering work on the PD-1 pathway, the Cancer Research Institute recently selected Drs. Sharpe, Freeman, Honjo, and Chen to receive the 2014 William B. Coley Award for Distinguished Research.

What's Next on the Cancer Immunotherapy Horizon From the Dynamic Duo?

PD-1 therapy is becoming the foundation for immunotherapy of cancer. "A multitude of labs including our own are building on that foundation and finding combinations with PD-1 that are even better," said Dr. Freeman.

PD-1, along with CTLA4 and TIM3, belongs to a group called immune checkpoint targets because they put the brakes on the immune system; in inhibiting these, the immune response can be reactivated to recognize and eradicate tumors.

Dr. Freeman is working on other molecules related to B7. Collaborating with the labs of Ana Anderson, PhD, and Vijay Kuchroo, PhD of the Brigham and Women's Hospital, his lab is currently working on TIM3—the T-cell immunogenic mucin—that is also a checkpoint target and is upregulated in tumors.

For Dr. Sharpe, microbes and tumors are the smartest players in knowing how to evade immune surveillance. "They are constantly finding new ways to do this. That's why it is important to target the "network of cues" collectively," she told Medscape Medical News.

For Dr. Freeman and Dr. Sharpe, the family business is thriving. They are both in the process of targeting immune checkpoints individually and in combination to determine the safest and most effective manner for switching off the brakes that tumors turn on to evade immune surveillance.


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