Jim Allison: Breakthrough Traces the Unexpected Creative Paths of a Scientist and Immuno-Oncology

Albert Einstein said, “The great scientists are artists as well.”¹ Leonardo da Vinci painted The Last Supper and was the first to define atherosclerosis.² Louis Pasteur’s love of art informed key theories on the shapes of crystals.³ Pure innovators transcend the lines between art and science, their creativity fuels the leaps forward, and their technical mastery brings ideas to life.

Such is the story of James P. Allison, PhD, the Texas immunologist who conceived during graduate school that T cells could have a role in fighting cancer—and then chased this idea to develop checkpoint inhibitors, part of the immunotherapy arsenal now called the fourth pillar of cancer treatment, with radiation, surgery, and chemotherapy.⁴

By the time Allison won a share of the 2018 Nobel Prize for Physiology or Medicine, the honor came as no surprise.⁵ But for years, this had been an end point few would have predicted from a gravely voiced, hard-partying outsider equally at home in the lab or onstage with his harmonica. This improbable journey now unfolds in Jim Allison: Breakthrough,⁶ a documentary from director Bill Haney that offers a portrait of an unlikely hero who dismantles stereotypes about science and scientists.

Breakthrough premiered in March at South by Southwest and opens in select cities on September 27, before a nationwide release on October 4.⁶ Haney spoke with Evidence-Based Oncology™ (EBO) about the film’s mission and his time working with Allison, who won the Nobel Prize the morning after principal filming ended in New York City. The film concludes with a shot of Allison getting the call from Stockholm; his son, Robert, filmed it in the New York City hotel where Allison was staying with his wife, oncologist Padmanee Sharma, MD, PhD, during a conference.⁷ Both are on the faculty at The University of Texas at MD Anderson Cancer Center. Allison is the Vivian L. Smith Distinguished Chair in of Immunology, director of the Parker Institute for Cancer Research, and the executive director of the Immunotherapy Platform; Sharma has a dual appointment as a professor in the Department of Genitourinary Medical Oncology and a professor in the Department of Immunology.

Haney hopes Breakthrough helps young people see scientists differently and to view them as creators in the same vein as actors or filmmakers. “In thinking about the creative landscape, we don’t include the scientists in the way their spectacular contributions justify,” he said in the interview. He set out to make a film on the immunotherapy revolution, and based just on the science, all roads led to Allison. The Nobel Prize came 7 years after the FDA approval of ipilimumab (Yervoy) to treat metastatic melanoma. Although the drug did not work in every patient, in those who responded, it brought results never before seen in a disease diagnosed in more than 65,000 people a year; at that time, melanoma deaths exceeded 9000 a year and were rising.^8,9

Then the director learned the tale of a boy from Alice, Texas. At age 11, Allison lost his mother to lymphoma. His grief-stricken father then abandoned him for stretches. In high school, his steadfastness that evolution was real got him the paddle and a boot from biology class. It became clear to Haney that “this was an extraordinary and unlikely hero.”

The story of Allison the creator, Haney said, comes not just from his love of music and people “but from thinking differently, from imagining how the T cell works differently.”

The film opens in Texas, where Allison grew up the youngest son of a family doctor and a beautiful mother who falls ill; Allison later learns it was cancer. His mother’s loss caused such upheaval that the school district paired young Allison with a family to stay with when his father was traveling. Haney’s curation of family photos and film snippets meant the South by Southwest premiere marked the first time Allison had seen footage of his mother carrying him lovingly as a toddler.

“There was a big hole, a lot of loneliness,” Allison says in the film, surfacing the hurt that seems fresh some 6 decades gone. Cancer later claimed the lives of 2 uncles as he grew up, before he built the traveling assembly of students and colleagues who have shared his pursuit of a cure.

MUSIC, AND WOMEN, AS CHAMPIONS

Allison also filled the void with his harmonica; to this day, he plays with fellow immunologists in their band, the Checkpoints. Winning the Nobel Prize also brought perks like playing with a fellow Texan, singer-songwriter Willie Nelson, and the film details Allison’s first encounter with Nelson at the dawn of the scientist’s research career in a California bar. Music, merriment, and the balance of working hard and playing hard are themes of Breakthrough. Allison builds fierce loyalty that one former student likened to a “pirate ship” while giving his team and himself bouts of “nonlinear” thinking to push their creative limits.

“Science isn’t the solitary life that most of us imagine it to be,” Haney told EBO. “Science is a social act, as well, and Jim is very skilled at that.… All of us are able to work harder with people we enjoy than with people we don’t enjoy.”

The atmosphere fueled Allison’s method of doing the hard experiments, the ones that work only if a theory is rock-solid, such as Allison’s insistence that a paper¹⁰ claiming the protein receptor CTLA-4 activated the immune response was incorrect. But it paid off on the fateful morning when Allison checked on mice given the antibody developed to shrink tumors based on the anti—CTLA-4 theory.¹¹ The tumors were gone. Now came the quest to turn the antibody into a cure.

If the loss of his mother left “a big hole,” the other women in Allison’s life have been his champions. Allison’s single-mindedness in getting the antibody that became ipilimumab approved took its toll, and during this period, he and his first wife, Malinda, separated after decades together. Malinda Allison is no longer Jim’s wife, but she is essential to Breakthrough; Haney said Malinda attended the premiere, where the director appreciated the deep, mutual respect between the former spouses. (The credits feature special thanks for Malinda Allison’s contributions.)

Midway through the film, Rachel Humphrey, MD, gives the pharmaceutical industry its warmest face ever when she describes leaving Bayer for Bristol-Myers Squibb (BMS), specifically to be the deep pocket behind the antibody Allison was developing with a small biotech company called Medarex.¹² Humphrey pulls no punches portraying the grief she endured after Pfizer canceled work on a competing immunotherapy, which signaled that the new drug class could be a failure.¹³

And Sharma is introduced in the film the way she met Allison—through the science. She ran an early clinical trial of ipilimumab, in which tumors quickly vanished for 3 of the 12 patients.¹⁴ “You never see this,” she says on-screen. “It’s like the pot at the end of the rainbow.”

FROM IMPOSSIBLE IDEA TO CURE

Ultimately, Breakthrough tells the story of science, and how the best science is about breaking paradigms. Allison first learned about T cells as an undergraduate at The University of Texas shortly after they were discovered in 1959¹⁵ and became fascinated with the idea that these soldiers of the immune system could someday fight the disease that had claimed his mother.

When the FDA’s approval for ipilimumab came in 2011,⁸ some 15 years had passed since Allison had proved that CTLA-4 acts as a brake on T cells.¹¹ A year later, while still at the University of California at Berkeley, he developed the monoclonal antibody that blocks CTLA-4, setting off the immune system to attack cancer.¹⁶ By this time, almost 3 decades had passed since Allison had shown up from Smithville, Texas, at a 1982 conference with a poster that identified the T-cell antigen receptor—the groundbreaking step that showed how T cells recognize invaders and upon which today’s most breathtaking therapies are built.¹⁷

As fellow scientists discuss in Breakthrough, Allison faced skepticism not just for his own ideas but also about immuno-oncology itself, after almost a century’s worth of attempts to turn the immune system against cancer had fallen short.^15,18 “Every time, it was met with disappointment,” Tyler Jacks, PhD, director of the Koch Institute, who is interviewed in the film, says in a preview.¹⁹

But Allison’s believers stayed true. Almost his entire lab followed him across the country from Berkeley to New York City when clinical trials for ipilimumab began at Memorial Sloan Kettering Cancer Center. Humphrey describes her own genetic predisposition to cancer and the family members she has lost. “The stakes are so high,” she says through tears. “Somehow it just didn’t matter when people yelled at me.”

Allison still boils over, years after ipilimumab has saved lived and changed cancer care, when he talks about the delays. “I knew this was a way to cure cancer, and I’ll be damned if I’m just going to let that lay around,” he says, seizing up at the memory of the search for financing. “I need to get it into people. I need to get it into patients.”

The urgency became personal. Allison’s brother died of prostate cancer in 2005, and he was given a diagnosis of the same cancer a week later.

FROM RISK TO REWARD

For a time, Medarex and its chief executive officer, Donald Drakeman, were making more headlines with mice than with medicine. Papers across the country carried a March 2000 Associated Press story about Medarex’s soaring stock price, which was based not on a drug it was developing but on its ability to make the immune systems of mice produce human antibodies.²⁰ Medarex had acquired the mouse technology along with a top scientist, Nils Lonberg, PhD, a few years prior, and Lonberg’s arrival would prove key in the biotech’s handshake deal to develop Allison’s antibody.²¹

In the early 2000s, Medarex and Drakeman were biotech darlings, but for every fan, there were skeptics. The business section of my former newspaper, the Times of Trenton, dutifully published the quarter-by-quarter losses for the company, which was based in nearby Princeton, New Jersey. “Sales ballooned but falling licensing revenues caused losses to skyrocket last quarter and last year,” began the March 19, 2003, article in which Drakeman warned, once again, that things would get worse before they got better.²²

It turns out that financials of immuno-oncology matched the biology. Breakthrough does an outstanding job of explaining how Allison, fellow scientists, and BMS not only had to develop a drug that worked but also had to persuade the FDA to develop a new paradigm for approving a drug that worked differently. Harnessing the immune system to take up the fight, instead of killing cancer with poison, means tumors will grow before they shrink; thus, approval should be based on overall survival. This was a tough concept, even for very smart people.²³

Which meant Allison couldn’t be just a scientist. He had to be a pain in the rear. And he was.

Matt Richtel of The New York Times is more tactful in the film. “You don’t know whether the new idea is something potent or deadly,” he says. “It takes a really powerful idea combined with someone willing to push it forward to make it happen.”

Skepticism followed ipilimumab at almost every step. On November 9, 2004, the day BMS announced it would invest $25 million with Medarex to develop the agent then known as MDX-010, BMS’ shares fell, at that point down 17% on the year.²⁴ On May 7, 2008, a month after Pfizer’s bombshell and weeks before the American Society of Clinical Oncology (ASCO) annual meeting, the FDA announced it wanted more data on ipilimumab. One analyst told reporters that ipilimumab’s ASCO data would have to outperform the antibody Pfizer had just abandoned for ipilimumab to be commercially viable.²⁵ The witnesses in Breakthrough testify that BMS’ decision to invest in more studies went against convention. BMS acquired Medarex not long after the FDA’s initial thumbsdown; an analyst said this was likely, given what the press called “Medarex’s string of drug failures.”^25,26

Allison knew better. Woven through Breakthrough is the story of metastatic melanoma patient Sharon Belvin, given a diagnosis and treated with chemotherapy days before her wedding at age 22. Ipilimumab’s ability to make her tumors disappear told Sloan Kettering oncologist Jedd D. Wolchok, MD, PhD, that something big was happening. Belvin is now cancer free, and she and Allison each share the story of the day they met at the clinic in 2006.

“Until then it was just numbers; it was a concept,” Allison says in the film. “She was the first patient.… Now she has a family, 2 beautiful kids.

“I still choke up when I think about that.”References

1. Calaprice A, ed. The Ultimate Quotable Einstein. Princeton, NJ: Princeton University Press; 2010:349.

2. Sterpetti AV. Cardiovascular physio-pathology by Leonardo da Vinci (1452-1519). Circulation Res. 2019;124(4):472-474. doi: 10.1161/CIRCRESAHA. 118.314390.

3. Gal J. Pasteur and the art of chirality. Nat Chem. 2017;9(7):604-605. doi:10.1038/nchem.2790.

4. McCune JS. Rapid advances in immunotherapy to treat cancer. Clin Pharmacol Ther. 2018;103(4):540-544. doi: 10.1002/cpt.98.

5. James P. Allison facts. The Nobel Prize website. nobelprize.org/prizes/medicine/2018/allison/facts/. Updated July 26, 2019. Accessed July 28, 2019.

6. Uncommon productions. Jim Allison: Breakthrough website. breakthroughdoc.com. Accessed July 28, 2019.

7. Caffrey M. Nobel Prize recognizes discoveries with T cells in immunotherapy. The American Journal of Managed Care® website. ajmc.com/focus-ofthe-week/nobel-prize-recognizes-discoveries-with-t-cells-in-immunotherapy. Published October 1, 2018. Accessed July 28, 2019.

8. 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 [news release]. Princeton, NJ: Bristol-Myers Squibb; March 25, 2011. news.bms.com/press-release/rd-news/fda-approves-yervoy-ipilimumab-treatment-patients-newly-diagnosed-or-previousl. Accessed July 28, 2019.

9. Guy GP, Thomas CC, Thompson T, Watson M, Massetti GM, Richardson LC; Centers for Disease Control and Prevention (CDC). Vital signs: melanoma incidence and mortality projections—United States, 1982-2030. MMWR Morb Mort Wkly Rep. 2015;64(21):591-596.

10. Linsley PS, Greene JL, Tan P, et al. Coexpression and functional cooperation of CTLA-4 and CD28 on activated T lymphocytes. J Exp Med.1992;176(6):1595-1604. doi: 10.1084/jem.176.6.1595.

11. Krummel MF, Allison JP. CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med. 1995;182(2):459-465. doi: 10.1084/jem.182.2.459.

12. Haas J. Bristol/Medarex: a transformational acquisition rooted in collaboration. Informa Pharma Intelligence website. invivo.pharmaintelligence.

informa.com/IV005175/BristolMedarex-A-Transformational-Acquisition-Rooted-In-Collaboration. Published September 18, 2017. Accessed July 28, 2019.

13. Pfizer announces discontinuation of phase III clinical trial for patients with advanced melanoma [news release]. New York, NY: Pfizer; April 1, 2008. pfizer.com/news/press-release/press-release-detail/pfizer_announces_discontinuation_of_phase_iii_clinical_trial_for_patients_with_advanced_melanoma. Accessed July 29, 2019.

14. Carthon BC, Wolchok JD, Yuan J, et al. Preoperative CTLA-4 blockade: tolerability and immune monitoring in the setting of a presurgical clinical trial. Clin Cancer Res. 2010;16(10):2861-2871. doi: 10.1158/1078-0432. CCR-10-0569.

15. Miller JFAP, Sadelin M. The journey from fundamental immunology to cancer immunotherapy. Cancer Cell. 2015;27(4):439-449. doi: 10.1016/j.

ccell.2015.03.007.

16. Leach DR, Krummel MF, Allison JP. Enhancement of the antitumor immunity by CTLA-4 blockade. Science. 1996;271(5256):1734-1736. doi: 10.1126/science.271.5256.1734.

17. Allison JP, McIntyre BW, Block D. Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody. J Immunol. 1982;129(5): 2293-2300.

18. Feinberg B. Issues impacting stakeholder adoption of immuno-oncology. Am J Manag Care. 2015;21(SP3):SP96-SP97.

19. Stories. Jim Allison: Breakthrough website. breakthroughdoc.com/stories. Accessed July 25, 2019.

20. Galewitz P. Living, breathing drug factories. (Panama City Beach, FL) News

Herald. March 26, 2000. newspaperarchive.com/panama-city-news-heraldmar-26-2000-p-44/. Accessed July 25, 2019.

21. Associated Press. Pfizer deal could be gravy train for smaller company. Times of Trenton. NJ.com. Published October 24, 2004. Accessed July 25, 2019.

22. Medarex losses shoot up. Times of Trenton. NJ.com. Published March 19, 2003. Accessed July 25, 2019.

23. Hoos A, Britten C. The Immuno-oncology framework: enabling a new era of cancer therapy. OncoImmunology. 2012;1(3):334-339. doi: 10.4161/onci.19268

24. Medarex, Bristol-Myers make deal. Times of Trenton. NJ.com. November 9, 2004. Accessed July 25, 2019.

25. Jordan GE. Drug’s delay a setback for many. Times of Trenton. NJ.com. May 7, 2008. Accessed July 25, 2019.

26. Bristol-Myers Squibb completes acquisition of Medarex [news release]. Princeton, NJ: Bristol-Myers Squibb; September 1, 2009. news.bms.com/

press-release/financial-news/bristol-myers-squibb-completes-acquisition-medarex-inc. Accessed July 29, 2019.

Download PDF: <i>Jim Allison: Breakthrough</i> Traces the Unexpected Creative Paths of a Scientist and Immuno-Oncology