The Nobel Prize: Checkpoint Inhibitors

Nobel Prize Recognizes Discoveries With T Cells in Immunotherapy

Mary Caffrey

Two scientists who separately uncovered mechanisms that block key proteins and allow the immune system to attack cancer, creating a new way to fight the disease, were awarded the 2018 Nobel Prize in Physiology or Medicine on October 1, 2018.

James P. Allison, PhD, of The University of Texas MD Anderson Cancer Center, and Tasuku Honjo, MD, PhD, of Kyoto University in Japan, were honored by the Nobel Assembly at Karolinska Institute in Sweden for work performed in the 1990s, which has resulted in FDA-approved therapies in the last decade.¹

Immunotherapy represents a new pillar in cancer treatment, alongside chemotherapy, surgery, and radiation. More than a century after scientists first conceived harnessing the body’s immune system to attack cancer cells, Allison and Honjo pushed science past the tipping point to develop the first commercial treatments that rely on this idea.

What makes immunotherapy such a game-changer, Allison said during a news conference in New York City, is that when patients achieve a durable response, it can last for years. For some, he said, the word “cure” is appropriate.

Called checkpoint therapy, such treatments act as accelerators that activate T cells, the white blood cells that send the immune system into battle, or as brakes, blocking the proteins that stop the T cells in their tracks. As the Nobel Assembly discussed in its announcement, “This intricate balance between accelerators and brakes is essential for tight control. It ensures that the immune system is sufficiently engaged in attack against foreign microorganisms while avoiding the excessive activation that can lead to autoimmune destruction of healthy cells and tissues.”¹

Allison, then at the University of California at Berkeley, was among scientists studying cytotoxic T-lymphocyte—associated protein 4 (CTLA-4). But while others looked at its potential in autoimmune disease, he looked at the potential in cancer. His lab resolved the issue of how the protein blocked the activation of

T cells, which was by opposing the stimulation needed from CD28 proteins. In experiments with mice, Allison showed that blocking CTLA-4 could boost T-cell responses. At first, tumors in the mice appeared to be progressing, but as Allison told the Journal of Clinical Investigation in 2015, the tumors for some mice stopped growing. “In the ones that had stopped, some of the tumors started necrosing, and they just went away.”²

His report in Science in 19963 eventually led to the development of ipilimumab. Allison worked with Princeton, New Jersey—based biotech firm Medarex to develop the human monoclonal anti- body. Bristol-Myers Squibb (BMS) later acquired Medarex, and in 2011, the FDA approved ipilimumab, the first therapy of its kind.⁴ Now sold as Yervoy, it was the first drug to extend the survival of patients with late-stage metastatic melanoma; study results show that 20% of the patients treated with ipilimumab live at least 3 years and many have lived 10 years.

Ipilimumab has been used in combination with therapies developed to target the protein that Honjo first studied in 1992, the programmed cell death protein 1 (PD-1), also expressed on the surface of T cells.¹ In a series of experiments at Kyoto University, Honjo showed that PD-1 also functions as a brake, but with a different mechanism. However, it took Honjo and his colleagues more than a decade to fully understand how this mechanism worked. In time, Honjo and a group led by Freeman et al, identified a ligand involved, programmed death-ligand 1 (PD-L1), raising the possibility that some tumors may use PD-L1 to inhibit an anti- tumor immune response. A 2005 paper by Honjo’s group showed that PD-1 inhibition may produce antitumor effects that are even more efficient than CTLA-4 and with fewer adverse effects.⁵

The work by Honjo’s team led directly to the development of nivolumab (Opdivo, BMS), which received approval in Japan in July 2014 and FDA approval in December 2014⁶; a second PD-1 inhibitor, pembrolizumab (Keytruda, Merck) received FDA approval in September 2014.⁷ One famous patient treated with pembrolizumab is former President Jimmy Carter, who celebrated his 94th birthday the same day the Nobel Prize was announced.⁸

Checkpoint therapy involving PD-1 inhibition is now approved to treat several types of cancer, including lung and renal cancer and lymphoma, besides melanoma. Many more clinical trials are underway involving many cancer types, including trials involving combination therapy. The next frontier is finding biomarkers to help pair these therapies with patients who will respond best to the drugs and to develop strategies to avoid adverse effects.

From his earliest experiments, Allison has strived to understand why these therapies work in some patients and not others, and he does this today through MD Anderson’s Moon Shots program, which analyzes tumor samples before, during, and after treatment.⁹ Honjo’s work also points out the importance of basic science, as his team was not searching for a pharmaceutical target when it discovered PD-1.

Allison was attending an immunotherapy conference when his son called at 5:30 am with the news. He said the recognition of the Nobel Prize will spread the message to patients with cancer that while other forms of treatment are still viable, combining them with immunotherapy offers the possibility of a cure for more people, even though there’s much work for scientists to do.

“We need these drugs to work for more people,” Allison said. “One challenge is that the clinical success has outrun our scientific knowledge of how these drugs work and how they might best be combined with other therapies to improve treatment and reduce unwanted side effects. We need more basic science research to do that.”

In a statement from MD Anderson,⁹ Allison thanked the patients who took part in early clinical trials. “I never dreamed my research would take the direction it has,” he said. “It’s a great, emotional privilege to meet cancer patients who’ve been successfully treated with immune checkpoint blockade. They are living proof of the power of basic science, of following our urge to learn and to understand how things work.”

REFERENCES:

1. The Nobel Prize in physiology or medicine 2018 to James P. Allison and Tasuku Honjo [press release]. Stockholm, Sweden: Karolinska Institutet; October 1, 2018. ki.se/en/news/the- nobel-prize-in-physiology-or-medicine-2018-to-james-p-allison-and-tasuku-honjo. Accessed October 2, 2018.
2. Hurst JH. Cancer immunotherapy innovator James Allison receives the 2015 Lasker-DeBakey Clinical Medical Research Award. J Clin Invest. 2015;125(10):3732-3736. doi: 10.1172/JCI84236.
3. Leach DR, Krummel MF, Allison JP. Enhancement of antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734-1736. doi: 10.1126/science.271.5256.1734.
4. FDA approves YERVOY (ipilimumab) for the treatment of patients with newly diagnosed or previously treated unresectable or metastatic melanoma, the deadliest form of skin cancer [press release]. Princeton, NJ: Bristol-Myers Squibb; March 25, 2011. news.bms.com/ press-release/rd-news/fda-approves-yervoy-ipilimumab-treatment-patients-newly-diag- nosed-or-previousl. Accessed October 2, 2018.
5. Iwai Y, Terawaki S, Honjo T. PD-1 blockade inhibits hematogenous spread 7. of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 2005;17(2):133-144. doi: 10.1093/intimm/dxh194.
6. Bristol-Myers Squibb announces US FDA approval of Opdivo (nivolumab) [press release]. Princeton, NJ: Bristol-Myers Squibb; December 22, 2014. news.bms.com/press-release/bristol-myers-squibb-announc-8. es-us-fda-approval-opdivo-nivolumab. Accessed October 2, 2018.
7. Merck receives accelerated approval of KEYTRUDA (pembrolizumab) the first FDA-approved anti-PD-1 therapy [press release]. Whitehouse Station, NJ: Merck; September 4, 2014. mrknewsroom.com/news-release/prescription-medicine-news/merck-receives-accelerated-approv- 9. al-keytruda-pembrolizumab-f. Accessed October 2, 2018.
8. Tontonoz M. Understanding Jimmy Carter’s surprise cancer turnaround. A conversation with Jedd Wolchok. Memorial Sloan Kettering Cancer Center website. mskcc.org/blog/understanding-jimmy-carter-s-surprise-turnaround-conversation-jedd-wolchok. Published December 9, 2015. Accessed October 2, 2018.
9. MD Anderson immunologist Jim Allison awarded Nobel Prize [press release]. Houston, TX: MD Anderson; October 1, 2018. mdanderson.org/ newsroom/2018/10/md-anderson-immunologist-jim-allison-award- ed-nobel-prize.html. Accessed October 1, 2018.

The Long Road: Nobel Prize Winner James Allison, PhD, Highlights the Value of Research

Allison Inserro

Nobel Prize winner James Allison, PhD, pioneering T-cell researcher, said the award represents the triumph of science and shows the value of research, even if that work does not immediately lead to a scientific or commercial success.

The soft-spoken researcher is sharing the award with Tasuku Honjo, MD, PhD. Both men were awarded the Nobel Prize for Physiology or Medicine on October 1, 2018, for their separate, but related, discoveries that uncovered mechanisms that block key proteins and allow the immune system to attack cancer, creating a new way to fight the disease.

Allison’s work led to checkpoint therapy, treatments that act as accelerators that activate T cells, the white blood cells that send the immune system into battle, or as brakes, blocking the proteins that stop the T cells in their tracks. The 70-year-old scientist is chair of the Department of Immunology, the Vivian L. Smith Distinguished Chair in Immunology, director of the Parker Institute for Cancer Research, and executive director of the Immunotherapy Platform at The University of Texas MD Anderson Cancer Center.

The day the Nobel Prize was announced, Allison spoke at a press conference in New York City held during the second day of the 4-day International Cancer lmmunotherapy Conference, run by the Cancer Research Institute, the Association for Cancer lmmunotherapy, the European Academy of Tumor Immunology, and the American Association for Cancer Research (AACR). Allison is a fellow of the AACR Academy and a former board member.

Allison said there are “somewhere on the order of 2000 clinical trials going on now with checkpoint inhibitors in combination with something else. And that something else is usually chosen just because a company owns it.” There are very few combinations based on data, he said.

There are also not enough patients in clinical trials, and given that, whether the result is a clinical signal or not, samples should be collected from every patient, he said. “You can understand something about a signal by knowing what didn’t happen,” he said.

He also noted that he thought there was too much emphasis in grantmaking for researchers to state “what the relevance is.” “How do you know what’s going to be relevant or not?” he asked. “I think you should pick your problem, work on it, do the best work you can.”

He spent his career studying cytotoxic T-lymphocyte antigen 4 (CTLA-4). His former lab at the University of California at Berkeley resolved the issue of how the protein blocked the activation of T cells, which was by opposing the stimulation needed from CD28 proteins. In experiments with mice, Allison showed that blocking CTLA-4 could boost T-cell responses. His work eventually led to the development of ipilimumab, now sold as Yervoy by Bristol-Myers Squibb.

Allison, who was woken with the news at 5:30 in the morning when his son called him, said he first started studying T cells in an immunology undergraduate course in Texas, about 50 years ago, when T cells had just been discovered. He asked the professor more about them after class, intrigued, and the professor replied that they float around the body and “do stuff.”

“I asked, ‘Well, how do they know what to do?’ He said, ‘I don’t know. I don’t know if they even exist,’” Allison recalled.

For deciding to make T cells his life’s work, Allison will split the $1-million prize with Honjo.

Joining Allison at the conference was Jill O’Donnell-Tormey, PhD, the chief executive officer and director of scientific affairs at the Cancer Research Institute, who called Allison a “dyed-in- the-wool” immunologist and noted that no one was interested in his work in the beginning.

Crystal Mackall, MD, conference scientific planning committee member and director of both the Stanford Center for Cancer Cell Therapy and the Parker Institute for Cancer Immunotherapy, called Allison a “role model for all of us” and said the average citizen needs to know more about why society needs to invest in basic science. “You make fundamental discoveries and it takes a long time,” said Mackall. But in the end, “you can cure people who are otherwise incurable.”

Allison, O’Donnell-Tormey, Mackall, and Nina Bhardwaj, MD, PhD, conference co-chair and director of cancer immunotherapy, professor of medicine, and Ward-Coleman Chair in Cancer Research at the Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, also spoke at the press conference about the future of immunotherapy.

Mackall and Bhardwaj echoed Allison’s comments about picking combinations to study based on data and science. Regarding chimeric antigen receptor technology, Crystal said, “We are just scratching the surface of what is possible” and thinks adoptive T-cell technologies will be able to treat solid tumors in the future.

Personalized immunotherapy will require biomarkers, O’Donnell-Tormey said. The expression of programmed death-ligand 1 on tissues as adjunct biomarkers for the intervention of antibodies is one such example, said Bhardwaj. Understanding the tumor environment and landscape will also be key, she said.

Another exciting future development, Bhardwaj said, is the discovery of neoantigens, arising from a patient’s specific mutations, which could help propel the creation of cancer vaccines and perhaps lead to cancer vaccines being combined with other methods.

Researchers are also focusing on understanding more about the concept of resistance, specifically T-cell resistance, and why they stop functioning, Mackell said. Bhardwaj said another type of resistance happens at the level of the tumor cells, where they learn to escape recognition by T cells.

“There’s an awful lot of biology that still needs to happen,” said O’Donnell-Tormey. She said the reason patients in clinical trials are asked to give so many biopsies is so that researchers have a grasp of what is happening at all phases, including before, during, and after treatment.

As for other predictions, Allison thinks that within the next 5 years some cancers are headed towards a 100% patient response, if they are given the right combinations. “Not many, but at least a few,” he said.

With immunology becoming the fourth pillar of cancer treatment, Allison said it “is the only one that can work nicely with the other ones,” and that has led to a shift in thinking. Instead of killing every last cancer cell, “just kill enough to let the immune system take it out,” he said.

The organizations did not have any warning that Allison would be awarded the Nobel, said O’Donnell-Tormey. “We’ve been anticipating for 3 years that he would get it,” she said.

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