VAN DEN EYNDE BENOÎT BRUSSELS LUDWIG Photo by Flynn Larsen 24 THE TUMOR DEFENSE DISMANTLER He began his career helping to lay the scientific groundwork for modern immunotherapy. Now he’s unraveling the myriad ways tumors thwart immune attack—and showing how to undo those defenses. In science, as in many other things, it’s the researchers expected the antigen would surprises that tend to stick with you—and be a randomly mutated version of a normal sometimes in more ways than one. gene—a neoantigen—which would appear foreign to T cells, provoking attack. “To Benoît Van den Eynde got a big one nearly our surprise, the antigen turned out to be three decades ago, while working with identical to the normal gene,” recalls Ludwig Thierry Boon, the founding director of the Member Van den Eynde. “We called it P1A Brussels Branch of the Ludwig Institute and realized quite quickly that the gene is for Cancer Research. Boon had previously expressed in the tumor but mostly silent shown in a series of milestone studies in the in normal tissues.” Reported in 1991, it was late 70s and early 80s that the mammalian the first of what would come to be called immune system can detect and clear cancer, the “MAGE-type” or “cancer testis” antigens, a possibility most scientists doubted at the which are expressed in human cancers as time. By the mid-80s, his team was racing to well and would become central to several find in mice and humans the first example immunotherapy strategies. of a naturally occurring cancer antigen, a molecular flag that marks diseased cells for P1A, for its part, stuck around as a useful targeting by T cells of the immune system. tool. Roughly a decade and a half later, Van den Eynde was working on the mice. Van den Eynde used it to construct a mouse model for an inducible cancer Based on their previous studies on tumors that provides a venue for a more realistic with chemically induced mutations, the assessment of immunotherapies. In 2017, 25 a year of credit in his clinical training for two “People are trying to spent on research and joined Boon’s newly opened Ludwig Branch in 1985. confirm those findings Based on its studies of mice, Boon’s team was by the mid-’80s creating what amounted but, if correct, spliced to personalized cancer vaccines for a small group of melanoma patients. The vaccines peptides will have to be worked quite well, even curing a German patient’s widely metastasized cancer—a landmark, if rarely repeated, event in the taken into account history of cancer immunotherapy. Van den Eynde, for his part, joined an effort to in vaccine design and identify the melanoma antigens and asked his medical school administrators for another two years to continue his research. Once across immunology.” again, his request was granted. In 1989, Van den Eynde published a paper in the International Journal of Cancer showing that the German patient’s T cells appeared he and his colleagues reported in Nature to target at least six naturally occurring Communications how they used that model antigens on her melanoma cells. Thrilled, to elucidate a novel mechanism of immune Van den Eynde dropped his medical studies resistance in tumors. In another study and, leading a small group by 1994, set about published in Cancer Immunology Research discovering antigens in melanoma and other in 2017, Van den Eynde and his team probed human cancers. He received his PhD in 1995. a separate mechanism of malignant immunosuppression and showed that it Over the next few years, Boon’s team raced might be overcome with the use of an anti- to translate its discoveries—particularly the inflammatory drug already on the market. MAGE cancer antigens—into cancer vaccines for more general use. Van den Eynde’s Becoming a scientist research, however, would take him down a When Benoît Van den Eynde was in high scientific path more fundamental in nature school near Brussels, his grandparents yet just as relevant to cancer immunotherapy. bought him a subscription to a science magazine. The gift opened his mind to Incisive science scientific discovery. “I thought, ‘This is a cool Sick cells alert the immune system to job to do,’” he recalls. their condition by chopping up abnormal proteins associated with their pathology and The thought stuck with him and, at 18, in his presenting the fragments, or peptides, to T second year of medical school at Université cells. The chopping is done by an enzymatic catholique de Louvain in Brussels, he asked machine known as the proteasome, the a biochemist if he could join his laboratory presenting by a family of proteins called MHC as a student researcher. After graduating (HLA in humans and H-2 in mice). In 2000, with honors with his medical degree, Van Van den Eynde’s group published a paper in den Eynde qualified for a five-year program Immunity describing a cancer antigen derived in internal medicine. But, still feeling the tug from a protein that was expressed in all cell of science, he exercised an option to claim types; the antigen seemed normal in every 26 Photo by Flynn Larsen way, yet it elicited a T cell attack only on vaccine design and across immunology,” says cancer cells, not healthy ones. Van den Eynde. “There was a paradox there,” says Van den His team also discovered that cancer cells Eynde, “and it was in trying to understand that tend to deploy a standard proteasome, while paradox that I became interested in antigen normal antigen-presenting cells express what processing.” is known today as the immunoproteasome— which is built from a different mix of Van den Eynde’s subsequent exploration of enzymatic subunits that generate distinctly the anomaly—which continues today—was different peptides for presentation. “If you rich with discovery. He and his colleagues want to trigger an immune response that is reported in 2004 in Science an entirely novel meaningful in cancer patients,” explains Van type of antigen processing, in which peptides den Eynde, “it would be better to trigger T are spliced and then shuffled so that their cells activated by peptides produced by the amino acid sequence no longer resembles standard proteasome.” any part of the original protein. A recent independent study suggested as many as La resistance a third of the peptides presented to T cells While exploring cancer antigens, Van den could be of that variety. “People are trying to Eynde also became increasingly interested confirm those findings but, if correct, spliced in the mechanisms by which tumors evade peptides will have to be taken into account in immune attack. In 1998, he came across a 27 Photo by Flynn Larsen paper showing that cells in the mammalian T cells almost entirely, rather than those in placenta help prevent T cell attack of the which IDO expression is induced by stimuli embryo by harnessing an enzyme known as such as immunotherapy. indoleamine 2,3-deoxygenase-1 (IDO-1), which deprives killer T cells of a vital nutrient—the Tumors of the former category were, in fact, amino acid tryptophan. Van den Eynde and a focus of the study Van den Eynde and his his colleagues reported in Nature Medicine in colleagues published in Cancer Immunology 2003 that tumors do the same. This sparked Research in 2017. Van den Eynde and his an industrywide race to develop IDO inhibitors colleagues suspected steady IDO expression as cancer therapies. Van den Eynde himself might account for the immunologic chill of launched, with Ludwig’s support, a spinoff such “cold tumors” and set about probing named iTeos—a story covered in the 2014 why it occurs. Their study revealed that the Ludwig Research Highlights report. steady expression of IDO depends on COX-2— an enzyme involved in inflammation—and its Unfortunately, the 2018 failure in Phase primary product, a long fat molecule named III trials of an IDO-1 inhibitor prompted prostaglandin E2 (PGE2). developers to pull back from the therapeutic class. But Van den Eynde remains optimistic PGE2, they showed, is produced by those that IDO inhibition still holds promise. A tumors and activates a signaling cascade better selection of tumors for IDO inhibition, within cells that triggers IDO1 expression. he believes, could improve efficacy in trials. Van den Eynde and his team showed in an It might, for example, work better in tumors immunologically reconstituted mouse model that continuously express IDO and lack killer of human ovarian cancer that blocking COX2 28 with a drug named celecoxib effectively shut down the constitutive expression of IDO-1 and “I thought, led to tumor rejection. ‘This is a “Celecoxib is already on the market, so you don’t need to do a drug development program before you test it in patients,” says Van den cool job to Eynde. Indeed, he is already in discussions with oncologists at the University Hospital do.’ ” Saint-Luc in Brussels about running a small clinical trial combining celecoxib and Photo by Flynn Larsen checkpoint blockade as a cancer therapy. Countering countersurveillance I was expecting that in this case the T cells Around the time Van den Eynde began mulling would be able to reject the tumor,” says Van IDO in the late 90s, he was also thinking den Eynde. “But they had no effect at all.” about how to develop a tumor model that might more faithfully recapitulate immune When the same P1A-expressing cancer suppression in tumors. Mouse models cells were transplanted into mice, however, available in the 90s were made by injecting they were cleared by ACT.