LUDWIG LAUSANNE: IMMUNOTHERAPY’S HI-TIDE George Coukos is all set to make Ludwig Lausanne a global pioneer in the development, delivery and evaluation of personalized, cell-based immunotherapies.

It was with some hesitation that George by,” says Coukos. “Here, I had them within Coukos first responded in 2011 to an reach, 25 minutes from the Ludwig Branch, invitation to consider moving to Lausanne. available and eager to collaborate.” On offer was the directorship of both a revamped Lausanne Branch of the Ludwig So it was that after several discussions Institute for Cancer Research and a proposed with Ludwig’s leadership and five trips Department of Oncology at Centre to Lausanne in which he met with the Hospitalier Universitaire Vaudois (CHUV) of leadership of UNIL, CHUV, and the the University of Lausanne (UNIL). Trouble Cantonment to ensure he’d have the was, he was quite happy at the University financial and institutional support he’d need, of Pennsylvania, where he had established Coukos was sold. His colleagues at Penn the Ovarian Cancer Research Center—a were astonished. “They tried very hard to prototype for linking basic, translational and persuade me not to leave,” recalls Coukos. clinical research in cancer immunotherapy. “ ‘George,’ they said, ‘this is career suicide, He was also a tenured professor and clinician what you’re trying to do. You’ll never be able at the prestigious university, with guaranteed to get it up and running in time.’ But here we tuition for his children, a dream house and no are, five years later, and we have built it all.” intention of ever leaving the United States. What Coukos and his colleagues have On the other hand, as he learned more about built is a rationally assembled, integrated the opportunity, it became increasingly system for swiftly devising, creating and clear that if he wanted to build a truly testing personalized immunotherapies pioneering program for developing advanced for individual cancer patients. It has two immunotherapies, Lausanne was just the core components. One is a network of George place for it. Coukos would find in CHUV translational research labs, housed primarily a sophisticated hospital and at UNIL and at Ludwig Lausanne, named the Human beyond a vast pool of researchers who would Integrated Tumor Immunotherapy Discovery be eager to participate in any such effort. & Development Engine, or Hi-TIDe. The Further, Lausanne is home to the Swiss other is the clinical arm of the endeavor, Coukos Federal Institute of Technology (EPFL) and the Centre for Experimental Therapeutics the Swiss Institute of Bioinformatics (SIB). (CTE), which is at CHUV. “The Hi-TIDe “These are two ingredients essential to the is responsible for the discovery and the development of advanced T cell therapies, development of new immunotherapies, and they’re extraordinarily difficult to come and the CTE is responsible for the clinical Photo by Eric Deroze 14 15 Adoptive T cell therapies offer an alternate route to stimulating immune attack. In these so far experimental therapies, a variety of TILs are extracted from a patient, selected for their cancer-detecting chops and then grown in the lab before they’re reinfused into the patient. Alternatively, T cells can be engineered to carry cancer- detecting antibody “warheads” before they are amplified and re-infused. The latter experimental treatments are known as chimeric antigen-receptor (CAR) T cell therapies.

Photo by Eric Deroze The Ludwig Lausanne effort aims to Lana Kandalaft streamline and accelerate the delivery of these therapies—and personalized cancer vaccines—to patients. “We are uniquely lab. He had even pulled together the support placed to translate advanced scientific he’d need to make that happen. Then he met hypotheses to the clinic,” says Coukos. “We Coukos, who described what he had in mind have secured the infrastructure to do so, for Ludwig Lausanne. “After half an hour with Photo by Eric Deroze Alexandre Harari which is not trivial because it requires deep George, I was like a groupie,” recalls Harari, scientific, technical and clinical expertise who is today a team leader of the antigen and integration, and it requires some very discovery unit of the Hi-TIDe and head of operations that bring them to the bedside,” is the enormous variability of cancer significant investments. All of these are now the Immune Monitoring Core Facility at the says Coukos. cells, which evolve and diversify as they in place.” CTE. “And then I did something extremely proliferate. Every cancer in every patient counterintuitive for a researcher: I returned The two units are now working in sync is in some ways a unique disease, with its Hi-TIDe’s FLOW my grants, and my fellowships, and I started to launch two clinical trials of advanced own set of characteristics, defenses and The Lausanne Branch, says Coukos, is devised in this new field of cancer research in which I immunotherapies, one that will test identifying molecular markers—or antigens. to serve science in the most unrestricted and had never worked before.” individualized cancer vaccines for ovarian Some common cancer antigens exist and creative way without losing its emphasis on cancer, and another that will evaluate researchers continue to try to develop more goal-oriented translational research. Similarly, Ludwig Lausanne’s Lana Kandalaft a personalized, adoptive T cell therapy general cancer vaccines on their basis. More “To do this, we’ve recruited top scientists moved from the University of Pennsylvania for solid tumors. “We want to transform often, however, every tumor is characterized who will be free and resourced to pursue to head the CTE. The unit, based at the immunotherapy, particularly as it relates by its own distinctive antigens. discovery and knowledge,” he says. But they CHUV’s Department of Oncology, which to T cell therapy, and believe strongly that do so in an environment that also provides Coukos directs, will run the upcoming clinical Lausanne can be one of the world’s pioneers Cells known as tumor infiltrating lymphocytes deep resources and mechanisms for the trials of personalized immunotherapies. It will in that arena,” says Coukos. (TILs) must recognize these antigens and clinical translation of their best ideas. They also provide tissue samples for the design of launch an attack. But telltale antigens might work very collaboratively, and in pursuit of those therapies, manufacture the cell-based THE CHALLENGE be hard to find. If found, the immune cells a common goal—developing personalized treatments in line with good manufacturing What makes immunotherapies so exciting must overcome a second major obstacle: immunotherapies and testing them in the practices, and monitor the anti-tumor to oncologists is that they train the body’s tumors usually evolve intricate defenses clinic. That goal has lured leading researchers immune responses of patients. Its facilities versatile defense systems—its immune cells— to snuff out such attack. Some of those to the center. have been inspected and approved by Swiss to detect and destroy cancer cells. Yet even defenses can now be countered by novel authorities. the most advanced immunotherapies in use drugs—like checkpoint inhibitors, a handful Alexandre Harari, for example, had by 2012 today fail to work in many patients, and fewer of which dismantle one of the brakes cancer established his reputation as an expert in Tumor samples from patients enrolled by still are curative. cells engage on threatening killer T cells. But the assessment of immune responses to HIV the CTE will make their way to the Hi-TIDe’s tumors often have many such defenses in infection and tuberculosis and was ready to antigen discovery unit, which is led by Harari There are many reasons for this. One play. leave his post at CHUV and start up his own and Michal Bassani-Sternberg, who joined 16 17 Photos by Eric Deroze Michal Bassani-Sternberg David Gfeller Melita Irving Steven Dunn

the Hi-TIDe from the Max Planck Institute. quickly identify the most clinically relevant secreted in tumors to destroy cancer cells, of the way. It’s all data driven and no two Working in the laboratory of Matthias Mann ones,” says Harari. Those cells can be grown or to counter the tumor’s inhibition of the projects are ever the same. That’s what gives at the Planck Institute, Bassani-Sternberg in large volumes for adoptive T cell therapy. immune response. me the buzz, actually.” pioneered methods to identify tumor Their T cell receptor (TCR) genes will also antigens using mass spectroscopy coupled be cloned to furnish data for scientific and “Engineered T cells can be used as miniature On the Hi-TIDe front, he says, the technology with sophisticated computational analysis. computational analysis and, later, T cell drug factories right in the tumor bed,” says is very well suited to T cell engineering. Like Harari, she was drawn to Ludwig engineering. Irving. “We are extremely excited about “We see this platform as being particularly Lausanne by the unique opportunity it offered the opportunity to use such cells in cancer well adapted to providing warheads for to translate her scientific innovations to the “The aim is to transfuse patients with T cells patients. In the future, CAR T-cells could CAR T cells,” says Dunn. It’s relatively clinic. She has teamed up with bioinformatics expressing the right TCRs,” says Harari. “This be customized based on the properties of a straightforward, he explains, to find and move and structural computational groups at can be done by many labs in a few months, patient’s tumor for truly personalized T-cell along an antibody gene for this purpose, the SIB and Ludwig’s own David Gfeller to but we are trying to optimize steps so that immunotherapy.” since it skips the more technically fraught identify antigens presented by tumors and we can do it within a few weeks of the patient and time-consuming business of developing pick out the ones most likely to excite a T cell arriving at the hospital.” To that end, Harari If Irving’s task is to engineer the T cell, Dunn’s a purified protein drug that can survive the response. has teamed up with advanced fluidic and is to identify and develop new antibodies manufacturing process. “What we’re working imaging bioengineers from EPFL’s Institute of that may be used for such engineering. At toward here is a rationally designed CAR Her team looks for both known cancer Bioengineering in Lausanne to develop new the heart of his antibody factory is a “library” factory.” antigens—such as melan-A, or the cancer technologies. of some 20 billion antibody fragments that testis antigens—and those that are unique to fit in a 1.5 mL tube. To isolate a binding MOBILIZING BASICS the patient’s cancer. “The advantage of this THE ARMORY antibody, his team sticks antigens of interest A more long-term effort of the Hi-TIDe technology is that we can really apply it to If the T cells are to be modified, this will be on beads and drops them into the library, involves a deeper exploration of the function, the individual,” says Bassani-Sternberg. “Off- done at the Hi-TIDe’s immune-engineering where antibodies can latch on to them. After and malfunction, of immune cells that are the-shelf vaccines [against a known cancer group, which is led by Melita Irving, an expert a few cycles of this, a number of antibodies found in tumors. That effort, a program antigen] may not be the best option for an on T cell engineering, and Steven Dunn, that bind firmly to an antigen remain on the in systems immunology, is led by Marie- individual patient.” who leads the Ludwig Antibody Core facility beads, and can be cloned, engineered further Agnès Doucey and Sylvie Rusakiewicz, and (LAbCore) of the Branch. Irving uses gene- and characterized. involves, among other things, probing how Bassani-Sternberg’s list of personalized engineering tools to equip T cells with natural T cells are dysregulated in tumors. Such antigens then moves along to Harari, who or synthetic receptors that can improve Of course, finding a useful antibody is like studies will guide interventions to overcome finds out which of them actually might be their targeting of tumors. Engineered T cells finding the needle in a haystack—far more tumor defenses and open new therapeutic useful. “There are distinct ‘flavors’ among can then be expanded and reinfused into complex than merely deploying a screen. “It’s opportunities. “The integration of that the T cells that recognize these antigens, the patient. Or they can be co-engineered not a push button procedure,” says Dunn. knowledge will fuel ideas to move into T and we are establishing a unique strategy to to express a variety of molecules that are “There are decisions to be made every step cell engineering down the line and suggest 18 19 Photos by Eric Deroze Marie-Agnès Doucey Sylvie Rusakiewicz Ping-Chih Ho Johanna Joyce

pharmaceutical interventions that could relevant to cancer immunotherapy, they Cancer Center in New York, where she reagent. It is, in fact, already collaborating improve the efficacy of T cell therapies,” says have a direct line to the translational led a world-class laboratory focused on on a couple of antibody projects with other Coukos. conduit of the Hi-TIDe. tumor macrophage biology. Her cutting Ludwig labs. “The idea is that we will not edge research on brain tumors and brain only supply George’s translational pipeline But studying human TILs in their native Ludwig Lausanne investigator Ping-Chih Ho metastases will inform key solutions for the in Lausanne but will also have a contributing microenvironment—and creating the has, for example, helped pioneer the study development of T cell therapies for such capacity for the global laboratories of experimental conditions required to learn of how immune cells are manipulated by tumors, which are extremely difficult to Ludwig,” he says. how to engineer them into living drugs— metabolic cues in the tumor. His previous treat. requires the development of surrogate work at Yale showed that cancer cells As for Coukos, an authority on ovarian systems that reproduce the tumor induce immune dysfunction inside some Though the Hi-TIDe team leaders tend cancer and a leading researcher in the field microenvironment in the culture dish. It tumors in part by hogging up glucose, a to be more goal oriented in their studies, of immunotherapy, the coalescing Lausanne also requires sophisticated technology that nutrient essential to killer T cell activity. they are all accomplished in their fields and Branch is the realization of a dream. “I’ve permits a deep yet swift and high-volume Ho says that specific subtypes of T cells many are collaborating with other groups been studying the tumor microenvironment analysis of small numbers of cells. Doucey are manipulated in unique ways in different on an array of basic research projects. and immune suppression for eighteen and Rusakiewicz are developing optimized tumor and tissue types, and his lab is Bassani-Sternberg, for example, is involved years,” he says, “and we now have the culture systems to do just that, studying trying to pin down those mechanisms and in a collaboration with the Branch’s opportunity to find solutions to some of human tumors using a systems approach that their consequences to inform targeted computational biologists David Gfeller and the biggest challenges to cancer therapy captures their extreme heterogeneity and therapies. Vincent Zoete. Together, they’re exploring posed by these factors. The resources here complexity. how an ocean of mass spectrometry data really enable me to do things that I could “You could engineer T cells to be resistant on the antigens presented to immune cells not do before.” Other investigators at Ludwig Lausanne feed to specific metabolic tumor defenses may be used to better predict such antigens into the Hi-TIDe, especially at this level. and reinfuse them into patients,” he says. in any patient. She is also investigating His integrated Hi-TIDe team is ready Coukos says that scientists recruited to lead “We’re also hoping to find drugs that why some tumors present more immune- to launch trials of the first therapies in independent groups at the Branch have the will rejuvenate anti-tumor T cell activity stimulating antigens than others and patients by the end of the year. “This is luxury of being unrestricted in their research, and synergize with T cell therapies or testing ways to boost the repertoire of such just the beginning of a long and exciting and are relatively free to pursue curiosity- checkpoint blockade.” Such strategies are antigens within tumors. journey” says Coukos. “We have set up the driven inquiries. But the researchers a natural fit for the systems immunology infrastructure to bring highly sophisticated themselves, he says, have been recruited and T cell engineering teams within the Dunn and his team, meanwhile, are eager therapies to the bedside, and now we are to Lausanne because their work might be Hi-TIDe. to apply their antibody and phage display ready to start testing some important of relevance to the long-term translational engineering platform to aid projects hypotheses on how best to reprogram goals of the Branch. Now, he notes, when Johanna Joyce joined the Ludwig Lausanne that might yield interesting therapeutic the immune system to fight and eradicate their discoveries look like they might be Branch from Memorial Sloan Kettering approaches or fill an unmet need for a critical cancer.” 20 21