Kai W. Wucherpfennig, PhD, Program Director, is the Chair of the Department of Cancer Immunology and Virology at DFCI and Professor of Neurology at HMS. His research focuses on the mechanisms of T cell mediated immunity, including antigen recognition by the T cell receptor and intracellular signaling. His current work emphasizes the discovery of negative regulators of T cell function in the tumor microenvironment (Nature 2014; 506: 52). His lab has developed an in vivo approach for discovery of targets for cancer immunotherapy using pooled shRNA libraries. He is the leader of the annual Cancer Immunology course at HMS and has taught in many other immunology courses, including the core immunology courses for graduate students (IMM201 and IMM202), the Critical Reading Course, the Seminar Course and the immunology section of the Cancer Biology course. He has served on the Admissions Committee of the Immunology Graduate Program since 1999 and chaired this committee for a three year term. Furthermore, he has served on the Immunology Graduate Committee since 2005, served a five year term on the Executive Committee for the Program in Immunology (2006-2011) and served for four years as co-chair of the Seminar Committee (2010-2014). He has also been very active in serving on the dissertation advisory committees and thesis defense committees of many graduate students.
Arlene Sharpe, MD, PhD, Co-Director, is the George Fabyan Professor of Comparative Pathology at HMS, Head of the Division of Immunology in the Department of Microbiology and Immunobiology, Leader of the Cancer Immunology Program of DF/HCC, Co-Director of the Harvard Institute of Translational Immunology and a member of the Department of Pathology at BWH. Her laboratory defined the in vivo function of T cell costimulatory and coinhibitory pathways in regulating T cell mediated immunity, in particular for the induction and maintenance of T cell tolerance as well as the induction of effective anti-tumor and anti-microbial immunity. In particular, she discovered the in vivo functions of the CTLA-4 and PD-1/PD-L1 pathways which are now targeted by FDA-approved antibodies for the treatment of cancer. In recognition of these decisive contributions, she shared the 2014 William B. Coley Award for Distinguished Research in Tumor Immunology from the Cancer Research Institute with Dr. Tasuku Honjo (Kyoto University School of Medicine), Dr. Lieping Chen (Yale University School of Medicine) and Dr. Gordon Freeman (HMS and DFCI). Drs. Sharpe and Wucherpfennig have for many years worked together in advancing immunology and cancer immunotherapy at HMS. For example, both serve on the Admissions Committee and the Graduate Committee of the Program in Immunology.
Ana C. Anderson, PhD is an Assistant Professor at BWH and HMS. She has discovered the important role of the inhibitory receptor TIM-3 in loss of T cell function in tumors. TIM-3 expression is induced in chronically stimulated T cells by the transcription factor T-bet, which is critical for interferon- production. TIM-3 thus represents part of an inhibitory feedback loop. She has shown that co-expression of PD-1 and TIM-3 marks a subset of highly functionally impaired T cells in tumors and that targeting of both molecules results in higher therapeutic efficacy in mouse models of cancer compared to monotherapy with either agent. TIM-3 is also expressed by tumor-resident regulatory T cells that are highly immunosuppressive. Based on these important advances, antibodies targeting TIM-3 are now in clinical development.
David Avigan, MD is Chief of the Section of Hematological Malignancies and Bone Marrow Transplantation at BIDMC and Associate Professor of Medicine at HMS. He has developed a novel personalized cancer vaccine approach in which patient-derived tumor cells are fused with autologous dendritic cells. This approach generates a hybridoma in which dendritic cells present a broad array of tumor antigens together with costimulatory molecules. In a phase 2 trial, 47% of patients achieved a complete response/near complete response, and vaccination resulted in an increased frequency of myeloma-specific CD4 and CD8 T cells. A randomized national phase 3 clinical trial led by Dr. Avigan is ongoing. He is also developing combination therapies that include vaccines, an example of which is a phase 1 study that assesses the response of patients undergoing vaccination with DC/myeloma fusions in the context of PD-1 blockade.
Vassiliki Boussiotis, MD, PhD is Professor of Medicine at BIDMC and HMS. Her lab studies the intracellular signaling pathways in T cells, with an emphasis on signaling mechanisms that prevent effective anti-tumor immunity. She has defined the key biochemical defects resulting in T cell anergy, a functional state in which T cells become unresponsive to antigen signals. These studies revealed that anergy represents an actively maintained genetic program in which the cell cycle inhibitor p27 and Smad3 play critical roles. She has also discovered key molecular and biochemical mechanisms by which PD-1 signaling alters T cell activation and cell cycle progression. In particular, she discovered that PD-1 signaling profoundly alters the metabolic state of T cells, with a shift from glycolysis to lipolysis and fatty acid oxidation. Her work emphasizes the study of such signaling pathways in human T cells which enhances the translational relevance of her work.
Harvey Cantor, MD is the Baruj Benacerraf Professor of Microbiology and Immunology at HMS and DFCI. He has made seminal contributions to the definition of functional T cell subsets, in particular the division of T cells into helper and cytotoxic subsets. More recently, he has defined a subpopulation of Qa-1 restricted CD8 T cells with regulatory function. A genetic mutation that impaired the functional activity of these regulatory T cells resulted in enhanced tumor immunity following vaccination. He has also defined intracellular signaling mechanisms that are important for formation of long-lived mature NK cell populations and showed that such NK cells are important for control of metastatic tumors.
Stephanie Dougan, PhD is an Assistant Professor in the Department of Cancer Immunology and Virology at DFCI. Her lab uses innovative approaches to develop novel animal models of anti-tumor immunity for mechanistic studies of cancer immunotherapies. She has used somatic cell nuclear transfer from tumor-infiltrating T cells to generate new mouse strains in which T cells carry a tumor-specific T cell receptor. Her laboratory is currently using this approach to generate mouse strains for neoepitope-specific T cells that spontaneously infiltrate tumors. Furthermore, her lab uses CRISPR/Cas9 genome editing to study the role of novel immunosuppressive genes.
Gordon J. Freeman, PhD is Professor of Medicine at DFCI and HMS. He is responsible for the discovery of PD-L1 and PD-L2 as the ligands for the PD-1 receptor on T cells. He demonstrated the inhibitory function of PD-L1 and PD-L2 on T cells and showed that blockade of this pathway enhanced T cell activation, proliferation and cytokine production. He also showed that PD-L1 is highly expressed by many solid tumors/hematological malignancies and that blockade of PD-L1 enhances killing of PD-L1 positive targets by CD8 T cells. PD-1 blocking antibodies have now been approved by the FDA for the treatment of melanoma and lung cancer. Dr. Freeman also discovered the B7-1 and B7-2 molecules (also referred to as CD80 and CD86) that bind to the costimulatory CD28 and the coinhibitory CTLA-4 receptor. He is thus responsible for key discoveries on the basic biology of costimulatory and coinhibitory pathways that led to the development of CTLA-4 and PD-1/PD-L1 antibodies for the treatment of cancer. He shared the 2014 William B. Coley Award for Distinguished Research in Tumor Immunology from the Cancer Research Institute with Dr. Tasuku Honjo (Kyoto University School of Medicine), Dr. Lieping Chen (Yale University School of Medicine) and Dr. Arlene Sharpe (HMS and BWH).
Wendy S. Garrett, MD, PhD is an Associate Professor at the HSPH. Her lab studies the interplay between the gastrointestinal immune system and gut microbiota in inflammatory bowel disease and colorectal cancer. It is well established that chronic inflammation predisposes individuals to the development of colorectal cancer. Dr. Garrett has shown that short-chain fatty acids (SCFAs) play a critical role in the homeostasis of regulatory T cells (Treg) that protect against colitis. SCFAs act through GPR43 and alter the expression of specific histone deacetylases in Tregs, thereby affecting Treg proliferation, population size and IL-10 production (a cytokine critical for protection against colitis). Her lab has also shown that Fusobacterium nucleatum accumulates in human colorectal cancers as well as human colonic adenomas relative to healthy surrounding tissues. In the ApcMin/+ mouse model of intestinal tumorigenesis, Fusobacterium nucleatum increases the number of tumors and induces recruitment of tumor-infiltrating myeloid cells that promote cancer progression.
Nir Hacohen, PhD is an Associate Professor of Medicine at MGH and a Member of the Broad Institute. He is a co-founder of the RNAi Consortium at the Broad Institute and has utilized unbiased genomic discovery tools to dissect innate immune pathways required for immunity to tumors and pathogens. He has used large-scale genomic datasets across 18 different human solid tumor types to discover key genetic changes related to cytotoxic T cell activity. He showed that the number of neoepitopes predicted to be presented by MHC class I molecules is correlated with cytotoxic T cell activity, and further showed that mutations in MHC class I pathway genes and caspase 8 represent key strategies for resistance to cytotoxic T cells. In collaboration with Cathy Wu (DFCI), he has pioneered the development of neoepitope vaccines, and this collaborative effort led to an ongoing phase 1 clinical trial of this innovative concept at DFCI.
Martin Hemler, PhD is Professor in the Department of Cancer Immunology and Virology at DFCI. His lab has made seminal contributions to our understanding of the role of integrins in migration of immune cells and tumor cells. He discovered and characterized the family of 1 integrins and described their role in adhesion to extracellular matrix proteins. He also discovered the 41 integrin which plays a central role during leukocyte-endothelial cell interactions and now is a major drug target. In addition, he showed that integrins can associate with CD151 and other tetraspanins which modulate integrin adhesion strengthening. Using CD151 knockout mice, he has described CD151 as a major contributor to pathological angiogenesis and tumor metastasis.
F. Stephen Hodi, MD is a Professor of Medicine (DFCI/HMS) and Director of the Center for Immuno-Oncology at DFCI as well as the Director of the Melanoma Disease Center at DFCI and BWH. Dr. Hodi led the clinical development of the CTLA-4 inhibitory antibody Ipilimumab and was the lead investigator of the phase 3 clinical trial that demonstrated the efficacy of Ipilimumab for the treatment of advanced melanoma. These results led to FDA approval of Ipilimumab (Yervoy) for the treatment of advanced melanoma in 2011. Particularly important was the demonstration that a subset of patients had a long-term durable response, despite advanced disease. The discovery that targeting of a single inhibitory receptor on T cells can induce a long-term protective response greatly energized the immunotherapy field. Dr. Hodi now has multiple ongoing clinical efforts aimed at discovery of highly active combinations involving Ipilimumab. He has shown in a phase II clinical trial that a combination of Ipilimumab and the cytokine GM-CSF enhances the efficacy and reduces the side effects of Ipilimumab monotherapy. Dr. Hodi also recently reported the enhanced efficacy of the combination of Ipilimumab with the PD-1 targeting antibody Nivolumab in BRAF V600 wild-type melanoma compared to Ipilimumab monotherapy. Dr. Hodi coordinates all immunotherapy trials at DFCI and plays a central role in studies that investigate mechanisms of responsiveness and resistance to immunotherapy.
Philip J. Kranzusch, PhD is an Assistant Professor in the DFCI Cancer Immunology and Virology and HMS Microbiology and Immunobiology departments. His lab uses a structural and biochemical approach to understand how immune cells use RNA second messenger molecules as a potent form of signal induction. A key example of RNA second messenger signaling is the enzyme cGAS (cyclic GMP–AMP synthase) that produces a dinucleotide RNA signal that activates the receptor STING and alerts the cell to the presence of pathogen- and tumor-derived DNA. Previously, Philip determined the molecular and evolutionary basis of human 2′3′ cGAMP signaling in the cGAS-STING response, and the lab is now working to determine the downstream steps of STING signaling activation and regulation. The long-term goal of the lab is to understand how RNA synthases activate human immunity, and explore the exciting possibility that RNA second messengers also control development and early cell fate decisions.
Vijay Kuchroo, DVM, PhD is the Samuel Wasserstrom Professor of Neurology at BWH and HMS. His lab has contributed critical insights into the molecular pathways that determine the functional specialization of CD4 T cells into distinct subsets. He has shown that there is a reciprocal relationship in the differentiation of naïve T cells into either FoxP3+ regulatory T cells or inflammatory Th17 cells. Using FoxP3-eGFP knock-in mice, he showed that TGFb, a cytokine abundantly produced by many tumors, induces regulatory T cells while the combination of TGFb and IL-6, an acute phase protein, induces Th17 cells. His lab also discovered the co-inhibitory TIM-3 receptor that is expressed by interferon-g secreting CD4 and CD8 T cells. In collaboration with Ana Anderson, he showed that TIM-3 marks the severely exhausted T cells in cancers. His lab is also discovering novel co-inhibitory receptors using systems biology approaches and has shown that both TIGIT and Podoplanin inhibit T cell responses.
Judy Lieberman, MD, PhD is a Professor of Pediatrics at HMS, Chair of Cellular and Molecular Medicine at BCH and a member of the American Academy of Arts and Sciences. Her laboratory studies the role of cytotoxic T cells and NK cells in tumor and antiviral immunity. In particular, she studies the molecular pathways used by these killer lymphocytes to induce programmed cell death in target cells. Dr. Lieberman has shown that each of the granzymes activates independent cell death pathways in target cells. Granzyme A also activates a DNase (GAAD), which nicks chromosomal DNA and acts as a tumor suppressor. Most recently, she discovered that killer lymphocytes can deliver an antimicrobial peptide (granulysin) into target cells which induces rapid death of intracellular bacteria, parasites and fungi. Dr. Lieberman has also performed groundbreaking work on the therapeutic delivery of siRNAs into immune and tumors cells. She developed targeted delivery methods to overcome the hurdle of siRNA delivery into immune cells.
Wayne A. Marasco, MD, PhD is a Professor of Medicine in the Department of Cancer Immunology and Virology at DFCI and a Professor of Medicine at HMS. His research interests are in the field of human antibody engineering and regenerative medicine. His lab uses human antibodies in discovery research and in the treatment of human diseases, and is also developing humanized mouse models for use in regenerative medicine and adult stem cell research. He works in two broad areas of infectious diseases and cancer immunotherapy, and he has discovered that human antibodies can not only be used to target proteins on the surface of cells and microbes but can also be used in the form known as intracellular antibodies (intrabodies), which can be delivered to cells by gene transfer techniques. He is also developing the construction and characterization of several of the largest human antibody phage display libraries ever made. Ongoing pre-clinical studies and clinical trials using human monoclonal antibodies are moving forward for the prevention and treatment of viruses such as influenza A.
Thorsten Mempel, PhD is an Associate Professor of Medicine at MGH and HMS. He has developed multiphoton intravital microscopy-based approaches to visualize the dynamic interactions of T cells in living mice with an intact blood circulation. Using these advanced imaging approaches, he is studying how regulatory T cells inhibit the anti-tumor function of cytotoxic T cells. In the absence of regulatory T cells, cytotoxic T cells (CTLs) kill their targets more than five-fold faster compared to regulated CTLs. Interestingly, regulated CTLs normally interact with target cells, but granule exocytosis and subsequent killing is significantly impaired. He further showed that Tregs locally remove costimulatory molecules from antigen presenting cells in tumors, thus inducing CTL dysfunction by altering the balance of costimulatory and coinhibitory signals that CTL receive. In mechanistic studies, he is using transcription factors labeled with fluorescent proteins to study how the dynamics of T cell interactions with different cell types determines transcriptional programs that drive T cell dysfunction and exhaustion.
David J. Mooney, PhD is the Robert P. Pinkas Family Professor of Bioengineering and a faculty member at the Wyss Institute for Biologically Inspired Engineering at HMS. Dr. Mooney has developed highly innovative biomaterials systems for therapeutic cancer vaccines. Induction of potent anti-tumor T cell responses requires presentation of tumor antigens by dendritic cells, but conventional dendritic cell based vaccines require complex ex vivo manipulation of cells which impair their efficacy. Dr. Mooney developed an implantable scaffold that effectively recruits dendritic cells (through release of GM-CSF) and programs them in an optimized microenvironment for induction of effective anti-tumor immunity (exposure to CpG oligonucleotide and tumor antigen). In animal models of melanoma and glioblastoma, this system generated potent protective immune responses. A phase 1 clinical trial is ongoing at DFCI for the treatment of stage IV melanoma. More recently, Dr. Mooney has developed an injectable system for creation of such vaccination microenvironments. Mesoporous silica rods injected with a needle spontaneously assemble in vivo and form macroporous structures that provide a 3D cellular microenvironment for host immune cells. This vaccine platform generates potent T cell and antibody mediated immunity.
Carl Novina, MD, PhD is an Associate Professor in the Department of Cancer Immunology and Virology at DFCI and an Associate Member of the Broad Institute. His lab studies the fundamental biology of microRNAs, their dysregulation in cancers and their use as biomedical tools. He demonstrated that an intronic microRNA (miR-211) is responsible for the tumor suppressor function of melastatin. He found that reduced miR-211, but not reduced melastatin, increases melanoma invasion and identified miR-211 regulated genes responsible for melanoma invasion and migration. He is currently developing innovative tools for studying the regulation of gene expression in tumors and immune cells. These include a single-cell RNA-seq platform to study gene expression by circulating tumor cells in melanoma as well as a highly innovative platform for epigenetic reprogramming in tumor cells and immune cells.
Mikael Pittet, PhD is an Associate Professor of Radiology at MGH and HMS. He utilizes advanced imaging technologies to characterize the in vivo behavior of macrophages that promote tumor growth. He has shown that the spleen can serve as a major source of immature myeloid cells, in particular precursors for tumor-associated macrophages and tumor-associated neutrophils. Recruitment of these immunosuppressive cell populations to tumors requires signaling through the chemokine receptor CCR2. Furthermore, he has shown that overproduction of the peptide hormone angiotensin II in tumor-bearing mice amplifies self-renewing hematopoietic stem cells and macrophage progenitors in the spleen. Blocking of angiotensin II production restrains such extra-medullary production of macrophages and inhibits tumor growth.
Francisco Quintana, PhD is an Associate Professor of Neurology at BWH and HMS. His lab studies how the nuclear aryl hydrocarbon receptor (AHR) induces an immunosuppressive program in both dendritic cells and CD4 T cells. AHR is activated by small molecules present in pollutants and the diet as well as small molecule metabolites, explaining how environmental factors can regulate immune responses. Cytotoxic T cell function in tumors is inhibited by two immunosuppressive CD4 T cell populations, IL-10 producing Tr1 cells and FoxP3+ Tregs. He has shown that AHR ligands can induce both immunosuppressive CD4 T cell populations. In FoxP3+ Tregs, AHR signaling induces expression of CD39, which converts immune-stimulatory extracellular ATP to highly immunosuppressive adenosine. He is now studying these important immunosuppressive pathways in the pathogenesis of glioblastoma.
Jerome Ritz, MD is a Professor of Medicine at DFCI and HMS. He is also the Executive Director of the Cell Manipulation Core Facility of the DF/HCC, a GMP cell manufacturing facility that provides a wide array of cellular products for bone marrow transplantation, cancer vaccines and adoptive cellular therapies. His research focuses on reconstitution and maintenance of donor immunity after allogeneic hematopoietic stem cell transplantation. He has demonstrated that donor immunity plays a critical role in elimination of residual tumor cells, referred to as graft versus leukemia (GVL). He has also studied the cellular mechanisms for graft versus host disease (GVHD) and documented a key role for both T cells and B cells. More recently, he demonstrated that FoxP3+ regulatory T cells are deficient in patients with GVHD, due to low telomerase activity and increased apoptotic priming. Based on these insights, he performed a clinical trial with low dose IL-2 to restore immune homeostasis in patients with GVHD. This approach results in clinical benefit in >50% of treated patients.
Margaret A. Shipp, MD is Chief of the Division of Hematologic Neoplasia at DFCI and Professor of Medicine at HMS. Her lab has made major contributions to our understanding of immunosuppressive mechanisms in lymphomas. She discovered the amplification of the two PD-1 ligand genes (PD-L1 and PD-L2) at 9p24.1 in patients with Hodgkin’s lymphoma and mediastinal large B cell lymphoma. This amplification also includes JAK2 which further enhances PD-1 ligand expression. She further showed that EBV infection is an alternative mechanism for PD-L1 expression in Hodgkin’s lymphoma and EBV+ post-transplant lymphoproliferative disorders. These discoveries led to a clinical trial of PD-1 blockade with Nivolumab in patients with relapsed and refractory Hodgkin’s lymphoma. An objective response rate was reported for 87% of patients which included 17% of patients with a complete response. Dr. Shipp has also shown that the malignant Reed-Sternberg cells in Hodgkin’s lymphoma overexpress and secrete galectin-1 which kills effector T cells and promotes immunosuppressive regulatory T cells. Antibody-mediated neutralization of galectin-1 prevents apoptosis of CD8 T cells, and a clinical trial is being planned.
Catherine Wu, MD is a Professor of Medicine at DFCI and HMS. She is a pioneer in the development of cancer vaccines that expand T cells that recognize tumor neoepitopes. These targets are exquisitely tumor-specific, being different from normal self-peptides. Her group initiated the first ever study of a personalized neoepitope vaccine, NeoVax (NCT01970358). In this ongoing phase 1 clinical trial patients with advanced melanoma and glioblastoma are vaccinated with a pool of long synthetic peptides representing patient-specific neoepitopes. Plans are underway to perform such trials in other cancers with a high load of predicted neoepitopes, including lung cancer and renal cell carcinoma. The importance of this trial is supported by previous data from her group showing that CLL patients who achieved long-term remission following allogeneic hematopoietic stem cell transplantation (HSCT) had long-lived cytotoxic T cell responses against peptides representing patient-specific neoepitopes.
Baochun Zhang, PhD is an Assistant Professor of Medicine at DFCI and HMS. He studies the pathogenesis of Epstein-Barr virus (EBV) induced lymphoma. In humans, EBV-infected B cells are under powerful immune surveillance by T cells and NK cells. If this immune surveillance is comprised, the virus can cause lymphomas. Dr. Zhang has developed a mouse model of EBV-induced lymphoma by transgenic expression of LMP1 which mimics a constitutively active CD40 receptor. Like human EBV-infected cells, LMP1+ B cells are efficiently eliminated by T cells, and breaking of immune surveillance results in rapid, fatal lymphoproliferation and lymphomagenesis. Surprisingly, LMP1+ B cells are primarily controlled by CD4 cytotoxic T cells. Dr. Zhang is now studying the molecular mechanisms responsible for CD4-mediated control of B cell lymphomas.