Professor James Allison

Born 7th August, 1948 (Alice, Texas, USA)

James Allison is best known for helping to elucidate the mechanism behind T cells activation and for pioneering the first immune checkpoint inhibitor drug for treating cancer. His work has radically transformed the landscape for cancer treatment, shifting it away from targeting a tumour to instead using the immune system to destroy cancer cells. He was awarded the Nobel Prize in Physiology or Medicine for this work in 2018.

James Allison at work in the laboratory in the late 1980s (Photo credit: James P Allison)

Family

Growing up with two older brothers Allison was by far the youngest. The age gap between him and his brothers was respectively six and eight years. They grew up together in Alice, a small backwater town where people were mostly employed in oil drilling. Their father, Albert, worked there as a country doctor specialising in eye, ear, nose and throat disorders and his mother was a housewife.

Allison’s life was touched by cancer from an early age. He was just 11 years old when he lost his mother, Constance, to lymphoma and by the time he was 15 one his uncles had died of lung cancer and another of melanoma. Many years later, in 2005, his oldest brother died of prostate cancer. A week after he buried him, Allison discovered that he too had prostate cancer and then a decade later that he had melanoma. In both cases Allison’s tumours were detected early enough for successful treatment.

By the time he was a teenager, Allison had already developed a strong sense of independence. In part this was due to the loss of his mother. It also stemmed from the fact that he was frequently left on his own by his father, who spent weekends away serving as flight surgeon for the Air Force Reserve, and by his older brothers, who were leading their own lives. Curious to find out how things worked, Allison spent a lot of his time dissecting frogs or building small explosives to set off in the local woods. He also had a rebellious nature which meant he often got into trouble at school for talking out of turn and truancy. Just how troublesome he could be can be seen from when he decided to boycott his biology class at high school after he learnt the teacher refused to teach evolution on religious grounds. Allison’s action caused such uproar the matter had to be referred to the school board. Eventually, with help of his father and his high school counsellor, Ernestine Glossbrenner, Allison was permitted to substitute the class with a correspondence course run by the University of Texas. Thereafter, he studied books alone in a separate classroom by the sports hall and carried out experiments by himself at home. This gave him a lot of experience at solving puzzles on his own. His rebellion nonetheless lost him a number of friendships and the support of some teachers. He was often taunted by a pupil or sports coach whenever they passed the classroom in which he was studying.(Blair, Cavallo)

Allison married Padmanee Sharma in 2014, a practising oncologist and researcher who left Guyana when a young child. She specialises in studying how tumours with different characteristics respond to immunotherapy. Allison and Sharma first met as research collaborators. In addition to sharing a passion for science, they both enjoy music.(Miller) Sharma often accompanies Allison to rock festivals where he plays the harmonica on stage. Allison is particularly fond of outlaw country music. One of his most treasured memories comes from 1975 when he gate-crashed a record party held by Willie Nelson, a fellow Texan and one of America’s most famous country musicians. To his delight Nelson invited him to play the harmonica with his band. He was again invited to do so in 2015. Allison regularly sings and plays the harmonica at immunology and oncology conferences with ‘The Checkpoints’, a rock/blues band made up of immunologists and oncologists from all over America that he helped set up in 2008.(Blair)

Education

Originally Allison contemplated becoming a doctor like his father. He began to change his views from the age of 13 after he became fascinated with science. His interest in the field was fostered by Glossbrenner, his school counsellor, and Stan Brooks, his maths teacher. Both teachers encouraged him to participate in a summer science-training programme funded by the National Science Foundation when he was 15. Run by the University of Texas in Austin, the programme included classes taught by Irwin Spear, an inspirational botanist. His lessons immediately hooked Allison on biology.

Allison graduated early from high school in 1965, when he was just 16 years old, and went to study at the University of Texas in Austin. Initially he was enrolled as a pre-med student, but he swiftly changed to science. His move was prompted by a part-time job he had washing glassware in the biochemistry laboratory of George Barrie Kitto. As he put it, ‘I realized that going the pre-med route meant memorizing a lot of information, and as a doctor, you can’t make mistakes—you have to know what to do. As a scientist, you are supposed to make mistakes and hypothesize, then test the hypotheses. To me, that was a hell of a lot more fun than following algorithms, so I dropped pre-med. Plus, my grades in organic chemistry sucked.’(Cavallo)

In 1969 Allison completed his undergraduate degree and enrolled for a doctorate in biochemistry at the University of Texas under the supervision of Kitto. According to Kitto it took some persuasion to get Allison accepted into the biochemistry department, because, as he said, ‘Jim’s grades were either A’s or F’s.... If Jim thought a class was useless, he just walked out and never bothered to drop it.’(Benson) Allison finished his doctorate in 1973.

Career

Following his doctorate, Allison spent three years as postdoctoral fellow researching molecular immunology at Scripps Clinic and Research Foundation in La Jolla, California. He returned to Texas in 1977 to take up a biochemistry faculty position at M.D. Anderson’s new Cancer Center Science Center, just outside of Smithville, where he remained for eight years. He subsequently went to the Cancer Research Laboratory at the University of California, Berkeley, to become professor of immunology and director of the Cancer Research Laboratory. In 2004 he moved again, this time to New York City, to head up the Ludwig Center for Cancer Immunotherapy at Memorial Sloan-Kettering Cancer Center. Eight years later he was appointed chair of immunology at the the M. D. Anderson Cancer Center.

Achievements

Right from the time when he was an undergraduate, Allison became intrigued by the immune system and decided to dedicate his life’s work to understanding how it worked. His interest in the area was deepened by one particular experiment he conducted on mice when a graduate student. He noticed that mice previously cured of leukaemia with an enzyme, asparaginase, rejected tumours when given a second injection of cancer cell cells. Based on this he wondered whether the immune system could provide a means to combat cancer. This he believed could provide a much more effective and less toxic form of therapy than radiation and chemotherapy, the devastating effects of which he had witnessed in both his mother and uncles.(Hurst)

By the 1970s Allison had developed a strong fascination for T-cells, soldiers of the immune system that help defend the body against foreign invaders. Encouraged by Ellen Ritchie, one of his colleagues at MD Anderson, he soon joined the worldwide scientific quest to uncover the mechanism that enables T cells to recognise molecules, or antigens, found on the surface of harmful substances.(Allison) A specific protein on the T cell was suspected to play a role in the process, but scientists were struggling to find it because they lacked the appropriate laboratory tools. It would be Allison and his team who discovered the first protein on the surface of the T cell. This they achieved in 1982 with the help of inbred mice and monoclonal antibodies.(Allison, McIntyre, & Bloch) Other proteins were found on T cells by other scientists shortly thereafter.(Benson, Lanier; Monika)

A decade later, in 1992, Allison and his colleagues demonstrated that T cells required a second molecular signal from a costimulatory molecule, CD28, to be fully activated and survive.(Harding, McArthur, Gross, Raulket, Allison) This was to be followed by another discovery in 1994. That year both Jeffrey Bluestone, an endocrinologist based at the University of California, San Francisco, and Allison separately established that another molecule CTLA-4 (cytotoxic T-lymphocyte-associated protein 4) could inhibit the activity of T cells. This protein had first been detected on the surface of T cells in 1987, but its function had puzzled scientists for many years.(Walnus, Bakker, & Bluestone; Krummel & Allison)

Based on the new evidence, Allison speculated whether blocking CTLA-4 could help unleash the power of T cells to attack and eliminate cancer cells. To test out his hypothesis, in December 1994, Allison began a series of mice experiments with Dana Leach, a postdoc in his laboratory. All the mice were initially injected with tumours and then divided into two groups. One was given a monoclonal antibody designed to block CTLA-4 and the other a control substance. Allison was totally unprepared for the result. While all the mice in the untreated group died, 90 per cent of those treated survived.(Miller) As he recalled, ‘I was expecting it [the anti–CTLA-4 antibody] to slow the tumors a little bit, but the tumors completely melted… I had to immediately set up the experiment again, to do all the injections, label the cages A, B, C, and D, and then go away and wait.... For a couple of weeks I was really depressed. I didn’t know which mice were which, but I could tell that all of the tumors were growing. Then, all of a sudden, it looked like some of the cages were progressing, but others just stopped. Then, in the ones that had stopped, some of the tumors started necrosing and they just went away.’(Hurst) Furthermore the blockade appeared to protect the mice against exposure to subsequent tumours. This suggested that blocking CTLA-4 had a long-lasting effect. Subsequent studies conducted by Allison in different animals showed that a blockade of CTLA-4, which they dubbed ‘immune checkpoint therapy’, was effective against a variety of tumours.(Leach, Krummel, Allison; Littman)

Excited by his findings with the mice, Allison patented the technique with the University of California, Berkeley, and began looking for collaborators to help him exploit the method further to develop a drug. Convincing others of his approach proved an uphill struggle. This in part reflected the fact until now most researchers in the cancer field had directed their efforts toward stimulating T cells with little success. Nobody had considered disrupting the inhibitory pathway that prevented such cells from responding to tumours.(Caputo; Sharma and Allison, Interview with Lonberg, Interview with Drakeman)

The situation changed after Allison met Alan Korman at a conference. Korman was an immunologist based at NeXstar Pharmaceuticals, a small biotechnology company. Following their discussions, NeXstar licensed Allison’s technique in 1998. A short time later Nexstar was acquired by Gilead Sciences and Korman persuaded Medarex, a small biotechnology company which he joined in 2002, to take over the license for Allison’s technique. Medarex was an ideal setting for the project because it possessed genetically modified mice for the production of fully human monoclonal antibodies. The mice had been perfected by Nils Lonberg while at GenPharm, a company bought by Medarex in 1997. By 2002 Lonberg had also transferred to Medarex. He and Korman already knew each other well having done their doctorates at Harvard University in the 1980s.(Interview with Lonberg).

Together with Korman and Lonberg, Allison set about developing fully human monoclonal antibodies to block CTLA-4. By 2001 they were ready to test one particular antibody, MDX-010, in humans. Prior tests in macaques had shown it be effective in blocking CLTA-4 and not to cause any harmful autoimmune effects. The first tests in humans were conducted by clinical investigators at the University of California, San Francisco. They carried out the phase I studies in two sets of patients. The first had hormone-refractory prostate cancer and the second metastatic melanoma. Encouragingly the therapy was well-tolerated by the patients and two out of 17 of those with melanoma had durable responses. Following this, a phase II trial was launched with advanced melanoma patients in collaboration with a team led by Steven Rosenberg at the National Cancer Institute. This again showed MDX-010, subsequently called ipilimumab, to be a promising agent for reducing tumours. In 2004 Medarex partnered with Bristol-Myers Squibb to extend the trials.(Littman)

By 2011 sufficient evidence had been collected from multiple clinical trials for the American and European regulatory authorities to approve ipilimumab (Yervoy) for adult patients with previously-treated advanced melanoma. Getting to this point had been a huge challenge because early on in the trials the drug was found to cause serious adverse inflammatory effects in trials, including colitis, hepatitis and hypophysitis. This was controlled with steroids. The investigators additionally struggled to prove the efficacy of ipilimumab. Part of the problem was the fact that patients who took ipilimumab initially experienced an increase in the size of their tumours and new lesions. This suggested the drug failed to halt the progression of their cancer. The turning point came when a number of the patients originally reported to have poor results went into remission. This mimicked the pattern Allison had observed in his very early mice experiments. Based on this the criteria for judging the drug’s efficacy was reconfigured to take account of the immune response to the drug rather than the shrinking of a tumour, which up to this time had been the conventional way for evaluating the efficacy of a cancer treatment. The work with ipilimumab laid an important foundation for how all other immunotherapies for cancer would subsequently be assessed.(Littman)

Having had his approach doubted for many years, the approval of ipilimumab was a major personal achievement for Allison. It also marked a breakthrough for the treatment of advanced melanoma. No new treatments had been approved for the disease in over 13 years. Even more important, it heralded the start of a new generation of cancer drugs - immune checkpoint inhibitors. Allison has not stopped work in the field. He is now hunting for clues to understand why it is that the immune system will attack cancer in some cases but not in others. Such research is important to pinpointing why not every patient benefits from ipilimumab and other checkpoint inhibitor drugs.(Allison, Parma and Allison)

Thanks go to James Allison for reading over an earlier draft of this profile written by Lara Marks,, August 2017.

References

J.P. Allison, ‘Checkpoints’, Cell, 162 (2015), 1203-05.
J.P. Allison, B. W. McIntyre, & D. Bloch, ‘Tumor-specific antigen of murine T-lymphoma defined with monoclonal antibody’, Journal of Immunology , 129/5 (1982), 2293-2300.
E. Benson, ‘The Iconoclast’, TexasMonthly, Nov 2016.
J. Blair, ‘Raising the tail’, Alcade, May/June 2014.
J. Caputo, ‘Two major cancer therapies may work better together, say researchers at MD Anderson’.
J. Cavallo, ‘Immunotherapy research of James P Allison’, The ASCO Post , 15 Sept 2015.
J.H. Hurst, ‘Cancer immunotherapy innovator James Allison receives the 2015 Lasker~DeBakey Clinical Medical Research Award’, Journal Clinical Investigation, 125/10 (2015), 3732–3736.
M.F. Krummel, J.P. Allison, ‘CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells’, Journal Experimental Medicine, 183 (1996), 2533–40.
L.L. Lanier, ‘First sighting of the elusive T cell antigen receptor’, Journal of Immunology, 174/3 (2005), 1143.
D.R. Leach, M.F. Krummel, J.P. Allison, ‘Enhancement of antitumor immunity by CTLA-4 blockade.’,Science, 271/5256 (1996), 1734-6.
D.R. Littman, ‘Releasing the brakes on cancer immunotherapy’, Cell, 162 (2010), 1186-90.
E.J. Monika, ‘Interaction of lymphocytes with antigen: Identification of antigen-specific receptors’ in E. Monika, ed, A historical perspective on evidence-based immunology (Amsterdam, 2016), 141-50.
J. Palca, ‘Cancer Scientist Jams With Willie Nelson One More Time’, NPR, 9 June 2016.
F.A. Harding, J.G. McArthur, J.A. Gross, D.H. Raulet, J.P. Allison, ‘CD28-mediated signalling co-stimulates murine T cells and prevents induction of anergy in T-cell clones’, Nature, 356/6370 (1992), 607-9.
K. Miller, ‘Beating Cancer at Its Own Game’, Discover Magazine, 27 Oct 2016.
P. Sharma and J. P. Allison, ‘Immune Checkpoint Targeting in Cancer Therapy: Toward Combination Strategies with Curative Potential’, Cell, 161/2 (2015), 205-14.
T.L. Walunas, C.Y. Bakker, J.A. Bluestone, ‘CTLA-4 ligation blocks CD28-dependent T cell activation’, Journal Experimental Medicine, 183 (1996), 2541–50.

James Allison: timeline of key events