Nobel Winner Created ‘Fourth Pillar’ in Cancer Treatment

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Cancer. The word is so ghastly that obituary writers invented code for it: “a long illness.” But this does not discount how common it is. We have all had a friend or relative who died of cancer—we may even know someone who died within weeks of showing signs of it. Even babies have it.

Jim Allison has extensive familial connections to it. He was only eleven when his mother Constance died from lymphoma. Within a few years, two uncles passed from it—one from lung cancer and the other from melanoma. Then prostate cancer got one of Jim’s older brothers. One week after his funeral, Jim found out that he had prostate cancer. He was lucky to catch this—and the melanoma he developed ten years later—in time.

These realities, combined with a childhood curiosity about science, pushed Allison to research immunological cures for cancer. He studied biochemistry as an undergraduate at the University of Texas, then decided to pursue a PhD rather than an MD, and completed postgraduate research at the Scripps Institute in California. Then, in 1977, he moved back home and joined the faculty at the M.D. Anderson Cancer Center at University of Texas.

In 2017, Time named him one of the 100 Most Influential People in the World; and just a few weeks ago, he and Tasuku Honjo of Japan earned the 2018 Nobel Prize in Physiology or Medicine for their work on drugs that interfere with cancerous cells’ defenses against the immune system’s T-cells, the disease-fighting white blood cells that develop from stem cells in the bone marrow. Certain cancerous cells, including melanomas, are vulnerable to T-cells; but the immune system is self-regulating so that it won’t go unchecked, attacking healthy cells along with the cancer. Another difficulty is the nature of a cancerous growth itself, which can elude detection by the immune system, and, if detected, summon up harmful mechanisms to defend itself. Allison and Honjo’s work better enables T cells in the body to kill malignant tumors.

The 2018 Nobel laureates also share the 2014 Tang Biopharmaceutical Science Prize for their work with two proteins that act as “checkpoints” along the immune system’s disease-fighting pathways: programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The latter is found on the surface of a T-cell capable of attacking cancer, but as a T-cell’s “go” or “don’t go” checkpoint, CTLA-4 suppresses the cancer-fighting response.

It was after winning the Tang Prize that Allison concentrated on the trial of ipilimumab, a CTLA-4 inhibitor first proposed in a 2012 paper he co-authored with two colleagues at the UC Berkeley Cancer Research Center. The possibility of such a drug had fascinated him for years, but the idea was met with much skepticism. Immunotherapy was deemed unlikely to become the “fourth pillar” of cancer treatment, alongside surgery (cut), radiation (burn), and chemotherapy (poison). According to Dr. Jedd Wolchok, a cancer specialist at the Memorial Sloan-Kettering Cancer Center, the two men have “brought immunotherapy out from decades of skepticism,” and their work has already “affected an untold number of people’s health.”

“The two men have ‘brought immunotherapy out from decades of skepticism,’ and their work has already ‘affected an untold number of people’s health.’”

Their success has been noted by PhRMA, which runs an ad portraying cancer immunotherapy as evidence of pharmaceutical industry innovation. But for many years, well-established pharmaceutical developers were reluctant to invest in the idea. In previous interviews, Allison has described his arduous quest to get ipilimumab—marketed as Bristol-Meyers-Squibb’s YervoyⓇ since 2011—into the hands of treating physicians.

At a 1996 conference, Allison managed to persuade Alan Korman, a scientist at the small Colorado biotech NeXstar Pharmaceuticals, to manufacture an anti-CTLA-4 protein, for which he granted rights under his patent. There are now five U.S. patents originated by Allison and his colleagues covering cancer immunotherapy formulations, methods to administer them, and combination therapies. Buf if you enter “Anti-CTLA” in the Patent Office search engine, it brings up fifty-nine related patents. There are 3,260 patents stating claims for formulations in the class of CTLA-4 or PD-1 affecting drugs for cancer therapy and more than 18,000 involving one or more cancer immunotherapy drugs and methods of creating and using them.

But Nextar couldn’t make a go of it, and parties disagreed over the return of the patent rights. “Try a new technology or give us the patent back,” Allison told the company. “They wouldn’t do either. I was really pissed.”

In 1998, NeXstar was acquired, and the patent followed with it. Korman and Allison regrouped, then joined forces with Princeton-based Medarex, which had technology for growing an anti-CTLA-4 molecule using mice genetically modified to have immune systems mirroring the human immune system. Medarex obtained rights to exercise the Allison patent.

Allison moved his base of operations to Memorial Sloan-Kettering in New York in 2004, where clinical trials of ipilimumab had begun. He wanted to be close enough to drive over and “be a nuisance.” Phase I clinical trials produced some, but not dramatic, results with prostate cancer patients, but remission in a melanoma patient with multiple metastatic tumors. Medarex had also joined with Pfizer on tremelimumab, another anti-CTLA-4 project. Trials for this drug were producing lesser results, and in 2008, Pfizer shut the project down.

A year later, Bristol-Myers-Squibb acquired Medarex, in time to shepherd ipilimumab through a Phase III trial. The FDA cleared the manufacture and distribution of ipilimumab for use in patients with inoperable or metastatic melanoma on March 25, 2011. Since then, the FDA has enlarged the drug’s permitted uses four times: for preventing secondary tumor formation in lymph nodes near the melanoma site; for pediatric use; for use in combination with a renal carcinoma immunotherapy; and most recently, for treating metastatic colorectal cancer.

The Houston Chronicle reported that Allison received a phone call from his son at 5:30 in the morning on the day that the Nobel winners were announced. Allison was at a conference in New York City. By 6:00 AM, colleagues were showing up at his hotel room with champagne. He and his wife, research partner Padmanee Sharma, hadn’t even had time to change out of their pajamas. Among the congratulatory phone calls was one from Willie Nelson’s band member and fellow blues harp player Mickey Raphael. And there was a call from Joe Biden, whose son Beau had been a patient at M.D. Anderson.

“Hey, Jim. Joe Biden. Well, I just wanted to congratulate you and thank you for everything you’ve done . . . We never gave up hope down at M.D. Anderson because of you and others. We kept hoping that time would outrun that god-awful glioblastoma. It didn’t, but you guys were wonderful. And I am so happy for you.”

That day, Allison also spoke with PBS News Hour. Toward the end of the segment, he spoke of how cancer tried to decimate his family and how this urged him on in. Two days later, he was interviewed for Texas Monthly, where writer Eric Benson posed an amusing question: “A couple of years ago, you told me that playing with Willie Nelson was more exciting than meeting the Pope. Now that you’ve won the Nobel Prize, which was more exciting: playing with Willie the first time or hearing that you’d won?”

Allison’s reponse? “That’s a difficult question, but I must say that getting the Nobel Prize is marginally better.”

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About Author

Jim Cahill retired in 2014 from practicing law first as an assistant New Hampshire attorney general and then in private practice. He has written for the Sunday Business section of the Concord Monitor, the Chicago Tribune’s digital media organization, Insulin Nation, and Type 2 Nation, where he also served as an editor. He has been a trustee, administrator, and compliance officer for national account employee health insurance and benefit plans and chairman of the governance committees on trustee boards of a secondary school and of a community senior health and activity organization. Jim has been managing type 2 diabetes since 1988, and in May 2018 was diagnosed with diffuse arterial disease.

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