MATCHMAKERS
Decipher the T-cell receptor cancer-recognition code
Dr Michael Birnbaum, Team Lead
Associate Professor of Biological Engineering
Massachusetts Institute of Technology
INSTITUTIONS
10
LOCATIONS
Germany, the Netherlands, Norway, UK, US
FUNDED BY
Cancer Research UK, National Cancer Institute, The Mark Foundation for Cancer Research
SPECIALISMS
cancer immunology, computer science, high-throughput method development, structural biology
Solving TCR recognition and design via integrated high-throughput screening, structural, functional and computational approaches
Funded by:
By harnessing advances in high-throughput approaches and computational prediction, MATCHMAKERS will take an integrated approach to understand and predict how T cells recognise tumours, paving the way for personalised immunotherapies.
T cells are central players in the immune response, and harnessing their power in the development of immunotherapies is transforming the treatment landscape for some cancers. However, despite the clinical success of immunotherapies, their effects are not universal across cancer types and patient subsets.
The molecular diversity of T-cell receptors (TCRs) has made it difficult to understand what tumour antigens are recognised by T cells, how T cells interact with the antigens presented by protein complexes on the surfaces of cancer cells (called major histocompatibility complexes or MHCs), and how these interactions differ in those who respond to treatment versus those who don’t.
To drive this understanding forward, MATCHMAKERS will develop novel methods and new algorithms, and create large, integrated datasets of TCRs and peptide-MHCs (pMHCs) to improve the understanding of the interactions between MHC-bound antigens and TCRs.
The team’s overarching goal is to predict what T cells recognise in individual tumours using simple laboratory tests and computational prediction, and develop the tools that can be used to design TCRs for personalised immunotherapies.
Tackling the T-cell receptors challenge
MATCHMAKERS will focus on three key aims:
Generate datasets to capture the diversity of TCR-pMHC interactions
An obstacle to computational prediction of TCR-pMHC interactions is a lack of data to train computer algorithms. But recent advances in high-throughput approaches mean that it is now possible to map the interactions between TCRs and antigens at scale.
MATCHMAKERS will use existing methods and develop new high-throughput approaches to match TCRs to the antigens they recognise, generating a dataset of thousands of TCR-pMHC pairs.
As well as collecting these datasets from naturally occurring sources of T cell responses, such as human clinical samples and mouse models in the context of both cancer and immunity more generally, the team will generate synthetic antigens and TCRs in the lab to identify new TCR-pMHC pairs.
Understand how TCRs and pMHCs interact at the structural level
TCR-pMHC pairing is based on the 3D structure of the binding sites on both the TCR and pMHC. Using structural and biochemical analyses, MATCHMAKERS will look at the 3D structures of TCRs and their pMHC targets to understand how the two proteins physically interact. This knowledge will allow for more accurate predictions of how TCRs and MHCs work together, and will enable these interactions to be better exploited for treatment.
Develop AI tools that can be used for TCR-pMHC prediction
The team will integrate the data it collects to develop and train cutting-edge computer algorithms that can predict the antigens that are recognised by different TCRs, and design new TCRs for use in immunotherapies.
MATCHMAKERS aims to transform the understanding of how an individual’s T cells recognise their tumour and revolutionise the creation of TCRs for personalised treatment approaches. If the team succeeds, the knowledge gained will have implications beyond cancer, such as for infectious diseases, autoimmunity and allergies.
Dr Michael Birnbaum, Team Lead
Associate Professor of Biological Engineering
Our team has the combination of immunologists, computer scientists and engineers needed to create the technologies to make it possible to predict what a T cell recognises, which will enable the development patient-specific TCR immunotherapies.
Plain language summary
In the past decade, there has been a revolution in the treatment of some cancers using therapies that harness a person’s immune system. These therapies, called immunotherapies, use the power of T cells – a type of white blood cell that are key players in the immune response to infection and cancer. T cells have receptors on their surfaces that recognise ‘antigen’ molecules that come from pathogens or cancer cells. After a T cell attaches to a cancer antigen, the cancer cell is ‘marked’ for destruction by the immune system.
Each of the millions of T cells in each person has a unique T-cell receptor that recognises different antigens. This diversity has limited our ability to know what exactly T cells recognise in the people who respond to treatment. If we can predict what cancer antigens a T cell ‘sees’ based on its receptor, we could find ways to create immunotherapies specific to each individual’s cancer and increase the overall effectiveness of these therapies across cancer types.
To bring us closer to this goal, MATCHMAKERS will collect data on T-cell receptors and the different antigens they interact with. Using this data and recent advances in artificial intelligence, the team will build computer models to predict the antigens that are recognised by different T-cell receptors. These predictions will be used to design T-cell receptors that are specific to an individual’s cancer.
If successful, MATCHMAKERS could transform the understanding of how an individual’s T cells recognise cancer cells from something that now can only happen in a few laboratories around the world, for a few people at a time, into a routine process. This will allow for better matching of patients with therapies that could lead to durable responses including remission and cure.
Michael is an immunologist and molecular engineer who has spent his career working to understand and manipulate T cell recognition. He has devised multiple technologies to study T cell recognition in high throughput, and combined them with computational approaches to better predict what T cells recognize in the context of cancer, infectious disease, and autoimmunity. His lab uses this information to design new therapeutic strategies to target tumors.
Michael completed his PhD in Immunology at Stanford University, and is an Associate Professor in the Dept. of Biological Engineering at MIT. He is a member of the Koch Institute for Integrative Cancer Resaerch, and of the Ragon Institue of MGH, MIT, and Harvard.
Organisation
Massachusetts Institute of Technology
David Baker is the director of the Institute for Protein Design, a Howard Hughes Medical Institute Investigator, the Henrietta and Aubrey Davis Endowed Professor in Biochemistry, and an adjunct professor of genome sciences, bioengineering, chemical engineering, computer science, and physics at the University of Washington. His research group is focused on the design of macromolecular structures and functions. Dr. Baker has published over 600 research papers, been granted over 100 patents, and cofounded 17 companies. Over 70 of his mentees have gone on to independent faculty positions. Dr. Baker is a member of the National Academy of Sciences and the American Academy of Arts and Sciences. He is also a project leader with The Audacious Project. He received his Ph.D. in biochemistry with Randy Schekman at the University of California, Berkeley, and did postdoctoral
work in biophysics with David Agard at UCSF.
Organisation
University of Washington
Regina Barzilay is a School of Engineering Distinguished Professor of AI & Health in the Department of Computer Science and the AI Faculty Lead at MIT Jameel Clinic. She develops machine learning methods for drug discovery and clinical AI. In the past, she worked on natural language processing. Her research has been recognized with the MacArthur Fellowship, an NSF Career Award, and the AAAI Squirrel AI Award for Artificial Intelligence for the Benefit of Humanity. Regina is a member of the National Academy of Engineering, National Academy of Medicine, and the American Academy of Arts and Sciences.
Organisation
Massachusetts Institute of Technology
Peter Bruno is an Assistant Professor in the Department of Urology and a member of the Helen Diller Family Comprehensive Cancer Center at the University of California, San Francisco. There he holds the Helen Diller Family Char in Basic Research in Urologic Cancer.
Peter and his team use synthetic biology and high-throughput functional genetic screens to expand our ability to interrogate and manipulate the immune system. Our new tools for understanding antigen presentation and T-cell recognition are being applied to cancer and other diseases with the goal of developing new immunotherapies and better implementing existing ones.
Organisation
University of California San Francisco
Professor Busch (b. 1966) conducts research into infection immunology with the goal of identifying therapeutically useful defense mechanisms. His work centers on antigen-specific T cells and the development of new technologies to make immune cells usable for diagnostic and cell therapy applications.
After studying medicine in Mainz and Freiburg (1993) and completing his doctorate (1993), Professor Busch commenced his clinical infectiological training in pediatrics (Würzburg, 1993-1996). He subsequently went to Yale University supported by a DFG scholarship (1996-1999). Having qualified as a lecturer in 2003, Professor Busch completed his residency in medical microbiology and epidemiology of infection (2005) at TUM. He heads the focus group “Clinical Cell Processing and Purification” at the TUM Institute for Anvanced study and co-initiated two sucessful start-ups (STAGE cell therapeutics GmbH and T Cell Factory B.V.). Prof. Busch is Chairman of the Board of the German Center for Infection Research (DZIF) and a member of the National Academy of Sciences Leopoldina. Since 2009, he has been Director of the Institute of Medical Microbiology, Immunology and Hygiene at TUM.
Organisation
Technische Universität München
Dr. Brandon DeKosky is an Associate Professor in the Department of Chemical Engineering at MIT and a Core Member of the Ragon Institute of MGH, Harvard, and MIT. Research efforts at the DeKosky lab have developed a suite of high-throughput single-cell platforms for large-scale analyses of adaptive immunity. These efforts are advancing new approaches in biologic drug discovery, and for cataloguing the vast genetic and functional diversity of adaptive immune cells in human disease settings. The group’s research includes mapping the T cell receptor targets of immunity against cancer, and the identification of precision antibodies with desired functional activities.
Dr. DeKosky has been awarded several honors for his research program. His Ph.D. research was supported by a Hertz Foundation Fellowship and an NSF Graduate Fellowship. In 2016, DeKosky was awarded a K99 Pathway to Independence Award and an NIH Early Independence Award. More recently he has also received a Department of Defense Career Development Award, the Biomedical Engineering Society Rising Star Award, the James S. Huston Antibody Science Talent Award, and the Amgen Young Investigator award.
Organisation
Massachusetts Institute of Technology
Professor Stephen Elledge is the Gregor Mendel Professor of Genetics and Medicine at Harvard Medical School. He has a long-standing interest in understanding the basis of genomic instability in cancer through cell cycle and DNA damage studies. He along with Dr. Wade Harper discovered the two largest families of E3 ubiquitin ligases, the CRL family initiating with the Skp1-Cul1-F-box E3 ligase family, and the role of RING domain E3 ligases. Dr. Elledge has developed a number of genetic technologies in mammalian systems to probe the adaptive immune response in B and T cells such as VirScan that allow the virome-wide detection of antiviral antibodies from a single drop of blood to determine the history of viral exposure; T-Scan and TCR-MAP to identify the targets of TCRs to identify epitopes on cancer cells.
Dr. Elledge’s research has been recognined by a number of awards including election to the National Academy of Sciences, National Academy of Medicine, and the Breakthrough Prize in Life Sciences, The Gruber Prize in Genetics, and the Albert Lasker Basic Medical Research Award.
Organisation
Brigham and Women’s Hospital, Harvard Medical School
Chris Garcia elucidated the structural framework for TCR recognition of pMHC, and pioneered diversity-based approaches to profile and engineer TCR specificity and cross-reactivity in TCR signaling. He has translated these findings to the clinic. For the Grand Challenge, the Garcia lab is focused on developing approaches for simulating TCR-peptide MHC diversity using in vitro evolution approaches.
Organisation
Stanford University
Johanna Olweus is Professor at the University of Oslo and Head of Department of Cancer Immunology, Institute for Cancer Research, Oslo University Hospital. She is an MD, PhD by training (University of Bergen) with a medical specialty in clinical immunology. Her training in transplantation immunology inspired her to work towards the goal of utilizing the powerful immune responses of graft-versus-tumor-reactivity and graft rejection to reject cancer cells in a targeted way. Olweus is pursuing this concept in her ERC Consolidator Grant project “Outsource”. Olweus was Director of the K.G. Jebsen Center for Cancer Immunotherapy 2013-19. The ambition to develop therapeutic TCRs directed at novel targets is pursued further in the newly opened (Research Council of Norway) Center of Excellence PRIMA – the PRecision Immunotherapy Alliance (2023 – 2033), for which Olweus is Director.
Organisation
Oslo University Hospital
Sergio Quezada is a Professor of Cancer Immunology and Immunotherapy at University College London Cancer Institute and Chief Scientific officer of Achilles Therapeutics. He earned his undergraduate degree in biochemistry from the P. Universidad Católica de Chile and a Ph.D. from Dartmouth Medical School in the US. In 2004, he joined the laboratory of the Nobel Laureate Prof James Allison at MSKCC, where he unveiled mechanisms underpinning the anti-tumour activity of anti CTLA-4 antibodies.
His work at UCL focuses in cancer immunology, tumour microenvironment, regulatory T cells and immune checkpoint blockade. His team’s research unveiled the critical role of Fc receptors and the tumour microenvironment in the mechanism of action of anti CTLA-4 antibodies, and he is an inventor of several key patents supporting the clinical development of antibodies targeting immune checkpoints including VISTA, ICOS and CD25. In the last few years, Prof Quezada and his team co-led the development of a first in class Treg-depleting anti-human CD25 antibody acquired by Roche in 2018 and is currently in clinical evaluation against solid cancers.
In addition to immune regulation, Prof Quezada’s research also aims to characterization and interrogate immune reactivity and function within the microenvironment of different human cancers, helping identify mechanisms of response and resistance to immunotherapy. His work in this area led to creation of a spin off company, Achilles therapeutics, a clinical stage company delivering personalised T cell therapies against cancer. In April 2020 Prof Quezada stepped in as Chief Scientific Officer of Achilles to lead the current and future scientific direction of Achilles.
Prof Quezada was a recipient of Dartmouth’s John W. Strohbern Medal for excellence in biomedical research, the Cancer Research Institute new investigator award, a CRUK Career Development Fellowship and a CRUK Senior Cancer Research Fellowship. In 2022 Prof Quezada was elected Fellow of the European Academy for Cancer Sciences
Organisation
University College London
Professor Ton N. Schumacher is a cancer immunologist known for his work that has established the important role of cancer neoantigens in the body’s natural response against cancer and in the clinical activity of cancer immunotherapies. In addition, his research group has created a number of widely used technologies to dissect T cell responses in cancer and other diseases. Through his work, he has also contributed to the development of adoptive T cell therapies and neoadjuvant cancer immunotherapy.
Ton is senior member at The Netherlands Cancer Institute, Professor of Immunotechnology at Leiden University, and Oncode Member. He is also, amongst others, elected fellow of the American Association of Cancer Research and the Royal Netherlands Academy of Arts and Sciences, and recipient of the Louis-Jeantet Prize for Medicine, AACR-CRI Lloyd J. Old Award, Meyenburg Cancer Research Award, and W.B. Coley Award.
Organisation
Netherlands Cancer Institute
Dr. Sgourakis earned his PhD in Biology from Rensselaer Polytechnic Institute in 2009, working with Angel Garcia on computational simulations of intrinsically disordered proteins, and a Master’s degree in Bioinformatics from the National University of Athens, Greece. As an undergraduate student, he developed machine learning algorithms for predicting properties of G-protein coupled receptors currently used in pharmacology and drug discovery.
In his first postdoctoral training with David Baker at the University of Washington, Dr. Sgourakis developed methods for modeling the structures of protein complexes by integrating NMR with cryoelectron microscopy data. During follow-up postdoctoral work with Ad Bax at the National Institutes of Health, he carried out Nuclear Magnetic Resonance (NMR) spectroscopy studies of virus/host protein interactions involved in immune evasion, and the establishment of latency, in close collaboration with the group of David Margulies.
With these skills in hand, he has developed an independent research program at the interface of biophysics and structural biology, where experimental and computational tools are developed and applied to tackle contemporary problems in molecular immunology and immuno-oncology. The long-term goal of the Sgourakis group is to develop novel targeted therapeutics to combat malignant brain tumors.
Organisation
The Children's Hospital of Philadelphia
