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An NCI-designated Comprehensive Cancer Center, affiliated with the University of Pittsburgh School of Medicine
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Oleg E. Akilov, MD, PhD, is an Assistant Professor of the Department of Dermatology at the University of Pittsburgh and a Director of the Cutaneous Lymphoma Program and Extracorporeal Photopheresis Unit. Dr. Akilov directs Cutaneous Lymphoma Program providing the full spectrum of management of all stages of cutaneous lymphoma. He serves as a principal investigator on multiple clinical trials in cutaneous lymphoma. Additionally, Dr. Akilov is very enthusiastic about resident education and mentoring future dermatologists.
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Dr. Bailey studies pediatric sarcoma biology. Specifically, Dr. Bailey's lab focuses on understanding the intersection of DNA damage and immunobiology in Ewing sarcoma. She is involved nationally in the Children's Oncology Group Bone Tumor Committee and is national Vice Chair of the COG clinical trial AOST2121.
Immunotherapy, specifically anti-PD1, has improved patient survival in a range of tumor types including head and neck squamous cell carcinoma (HNSCC) and non-small cell lung cancer (NSCLC). Despite the success of anti-PD1 therapy, only 20% of patients produce a durable response to this treatment. Further, there are some solid tumor types i.e. ovarian cancer, which yield very little therapeutic benefit from current standard of care immunotherapies. Thus, a need exists to develop additional therapeutic strategies to treat these patients, which includes evaluation of other tumor infiltrating immune cells that could further augment the CD8+ and CD4+ intratumoral T cell response. B cells represent a possible target for immunotherapy due to their predominance in the tumor microenvironment (TME) and crucial role in the immune response. However, B cell function in cancer and in the context of immunotherapy has been understudied. In fact, conclusions on an anti- or pro- tumor role for B cells in the TME remain incomplete. However, in multiple solid tumors, current evidence suggests an anti-tumor role for B cells. Specifically, detection of B cells within tertiary lymphoid structures (TLS) correlates with increased survival and immunotherapeutic response. While B cells have been identified in multiple tumor types, their complete phenotypic signature and interplay with other components within the TME have been understudied. Further, the complex composition of TLS in patient tumors is severely underappreciated, which is an overt focus of the Bruno laboratory. Specifically, we aim to understand B cell infiltration and TLS development within solid tumors to generate effective B-cell focused immunotherapies to augment the current successes of standard of care immunotherapies such as anti-PD1.
To this end, we take a multi-level approach to understanding B cells and TLS composition in human tumors. Specifically, we transcriptionally assess B cells via single cell RNAseq with paired BCR seq, we interrogate B cell subsets within patient tumors using multi-parameter flow cytometry (15-30 parameters), we locationally evaluate B cells within and outside TLS utilizing multispectral imaging (Vectra Polaris) and spatial transcriptomics (Nanostring GeoMax Digital Spatial Profiler), and we evaluate the function of B cells and their interplay with other important immune cells within the TME via micro-scale in vitro functional assays.
Dr. Bunimovich is a faculty member of the Department of Dermatology at the University of Pittsburgh and the UPMC Hillman Cancer Institute, and a graduate faculty member in Molecular Pharmacology and Cellular & Molecular Pathology. He obtained PhD in Chemistry and Chemical Engineering from the California Institute of Technology, and MD from UCLA where he also completed postdoctoral fellowship in tumor immunology at the Crump Insitute for Molecular Imaging. Dr. Bunimovich's research program is focused on the neuroimmune regulatory mechanisms of cancer progression, with the emphasis on the roles of sensory neurons and neuroglia in the modulation of melanoma immunosurveillance. His laboratory is also investigating mechanisms of ferroptosis in cutaneous pathophysiology. His work is funded by the NIH/NCI, the American Cancer Society, the Skin Cancer Foundation, the American Skin Association. Dr. Bunimovich practices general medical and surgical dermatology, including treatment of cutaneous malignancies, atopic dermatitis, psoriasis, autoimmune, immunobullous and other skin conditions.
In the Byersdorfer lab, we study immune cell metabolism in T cells during graft-versus-host disease (GVHD) and in the immune response to cancer. The goal of the lab is to define metabolic pathways up regulated in T cells causing GVHD, to shut them down, while leveraging our knowledge of the same or similar metabolic pathways to augment anti-cancer responses, particularly in vivo. We use animal models, genetically modified donor cells, and single cell technologies to ask fundamental questions regarding in vivo T cell metabolism. Excitingly, we have recently expanded our studies to investigate metabolic pathways specifically in GHVD-causing and cancer-fighting human T cells. Our current work falls into three categories: basic science investigations into novel pathways of in vivo T cell metabolism, translation of GVHD-targeting therapies to human T cells, and augmentation of human T cell driven, anti-cancer immune responses.
In recent years, the decades-long promise of tumor immunotherapy has finally begun to come to fruition. Checkpoint blockade, for example, represents a critically important intervention for potentiating the antitumor immune response. In these therapies, blockade of T cell intrinsic negative regulators (such as CTLA-4 and PD-1 signaling) releases the brake on effector T cells in the tumor, resulting in substantial, durable antitumor immunity, and clinical responses.
While negative regulators on the effector T cells can be relieved through these interventions, effector T cells still face a variety of cell extrinsic modes of immune suppression, notably through suppression via regulatory T (Treg) cells. Treg cells play critical roles in preventing autoimmune responses to self tissues as well as limiting immunopathology during exuberant immune responses. However, Treg cells represent a major barrier to antitumor immunity. Many tumors recruit, activate, and expand large numbers of Treg cells, which can be specific for any number of normal, self antigens expressed by the tumor. While depletion of total Treg cells can result in autoimmune pathologies, inhibition of Treg cell stability or function has been shown to allow for local inhibition of Treg cell suppression in the tumor, while sparing normal tissues from an autoimmune response.
Thus, finding phenotypic, signaling, or functional parameters that distinguish intratumoral Treg and conventional T (Tconv) cells could shed light on mechanisms by which Treg cells could be targeted to allow for a greater antitumor response. Recent studies have found that Tconv and Treg cells have distinct metabolic requirements. Not unlike cancer cells, conventional T cells undergo aerobic glycolysis (the 'Warburg effect') when undergoing robust expansion. However, regulatory T cells utilize alternative sources of fuel. Our initial findings in the laboratory suggest that not only do intratumoral Treg cells utilize distinct fuel from their conventional brethren, but engage different metabolic pathways from Treg cells in normal tissues and lymphoid organs. This suggests that metabolic pathways, or their downstream targets, could be targeted in order to inhibit intratumoral Treg cells specifically, releasing a crucial cell extrinsic brake on the antitumor immune response. The goal is to provide alternative modalities of therapy that could be utilized alone or in combination with other immunotherapeutic strategies, to allow for robust and durable immune responses for the eradication of cancer.
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Dr. Edwards' research interests include the treatementHPV-related and ovarian malignancies with immunotherapeutic approaches. He serves as principal investigator for a number of pharmaceutical-sponsored studies. He also serves on the Cancer Vaccine Committee, which experiments with novel therapeutic approaches to gynecologic malignancies and produces translational research.
Three specific targets of Dr. Edwards' research include: 1) vaccine therapies for cervical and ovarian cancer; 2) combining biologic and immunologic therapies with traditional therapies in the treatment of women's cancer; and 3) intraperitoneal therapy.
Dr. Falo is actively involved in a variety of research projects focused on the prevention and treatment of melanoma and skin cancers, and has research expertise in the areas of cutaneous drug delivery, radioprotection, immunobiology, vaccine design, antigen processing and presentation, dendritic cell biology, and molecular immunobiology and immunotherapy.
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Dr. Ferris's laboratory is focused on understanding basic immunological mechanisms of the lymphocyte response to cancer,including T cells and natural killer (NK) cells, for the development of novel immunotherapeutic approaches to head and neck cancers (HNC). Tumor immunotherapy and vaccine clinical trials are currently underway and new strategies are in development, focused heavily on neoadjuvant “window of opportunity” trials. We are particularly interested in the immune response to a distinct subgroup of head and neck squamous cell carcinomas caused by human papillomavirus (HPV). Monitoring the successful immune effects of individuals treated with immunotherapy is a major effort, using single cell transcriptomic, proteomic, spatial technologies. We are also studying tumor induced immune evasion, such as defective antigen processing/presentation and alternative immune checkpoints to subvert T lymphocyte recognition of tumors. Our studies are funded by multiple NCI R01 and SPORE grants as well as extensive collaborations with biotech and pharma to investigate mechanisms of therapeutic activity or resistance to clinically available immune-oncology (I-O) agents currently in the clinic. Validation in animal models is a parallel effort once mechanism(s) are identified in clinical specimens of I-O treated patients.
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The long-standing interests of our laboratory center on identifying specific mechanisms of human anti-tumor immunity and cancer immunosurveillance. We study T cell and antibody repertoire in cancer patients and in healthy individuals at risk for cancer and factors that influence that repertoire. We were the first to identify a human tumor antigen recognized by human T cells and antibodies, the epithelial mucin MUC1. We showed that tumors express an abnormal form of MUC1 that is recognized by the immune system as a foreign rather than a self-antigen. Studies in mice and primates showed that MUC1 was immunogenic and that anti-MUC1 immune responses can reject tumors. These studies supported multiple clinical trials of a MUC1 vaccine in patients with breast, colon, and pancreatic cancer. Most recently, we began testing a MUC1 vaccine for cancer prevention in individuals diagnosed with MUC1+ premalignant lesions. In addition to being a tumor antigen, MUC1 is an oncogene by virtue of promoting a highly inflammatory tumor microenvironment. We discovered that the tumor form of MUC1 activates NF-kB, binds p65 and translocates to the tumor cell nucleus where it binds to and activates promoters of inflammatory cytokines, such as IL-6 and TNF-a. MUC1 has been associated with a more invasive cancer phenotype and we have recently deciphered the mechanism by showing that it forms complexes with CIN-85, also previously associated with cell motility and invasion.
While studying MUC1 and another tumor antigen that we discovered, cyclin B1, we made an important observation that many tumor associated antigens (TAA) described by their abnormal expression on cancer cells, are also abnormally expressed in other acute or chronic inflammatory conditions and are therefore more appropriately defined as disease associated antigens (DAA). These include bacterial infections such as Mumps, viral infections such as chicken pox, and chronic inflammations such as inflammatory bowel disease (IBD). This observation helped us formulate and test a new hypothesis on cancer immunosurveillance. Working in collaboration with epidemiologists and creating appropriate mouse models, we showed that immunity to abnormal self-antigens, DAAs, is generated simultaneously with immunity to pathogens early in life in the course of febrile infections. Immune memory for DAAs contributes to effective immunosurveillance of other pathogen infections throughout life, as well as of cancer that expresses many of those same antigens. Lastly, we are pursuing an idea that the quantity and the quality of immune memory for DAAs is critical for maintaining general immune health. Using genomic and bioinformatics approaches, we are defining a gene expression signature that characterizes individuals with strong immunosurveillance ability versus those that lack that ability and designing DAA-based vaccines to promote immunosurveillance of cancer and other diseases.
I am an assistant professor of immunology at the University of Pittsburgh and member of Tumor Microenvironment Center at UPMC Hillman Cancer Center. My research focuses on the mechanisms that control cell death and how the quality of cell death can modulate the immune response, especially anti-tumor immunity. I have actively pursued research in cell death and immunology for fifteen years, at Beijing Normal University and National Institute of Biological Sciences, Beijing, China as a graduate student, St. Jude Children’s Research Hospital as a postdoc, and the University of Pittsburgh as principal investigator.
My work has initially focused on apoptosis/apoptosome and pyroptosis/inflammasome activation in macrophages, monocytes, and dendritic cells. I have identified bromoxone as a pan-inflammasome inhibitor and revealed mechanisms of inflammasome action against bacterial pathogen infection. I continued working on the programmed cell death, mainly necroptosis; I discovered the role of ESCRT- III in necroptosis and its immune responses. ESCRT-III machinery can rescue the necroptotic cells via shedding and repairing broken plasma membrane, thus, sustain cell survival. As a consequence, cells undergoing necroptosis can express chemokines and other regulatory molecules to promote dendritic cell-mediated cross-priming of CD8+ T cells. In collaboration with clinical investigators, I revealed ESCRT-III keeps cells from lysis, especially in kidneys from the transplantation procedures.
After becoming an independent researcher, I continue to work on the mechanisms of programmed cell death and its role in regulating immune responses, including auto-immunity and cancer immunology. We keep exploring novel signaling pathways of programmed cell death. We are also focusing on new drug target discoveries in the cell death pathway. Our goal is to use these targets to overcome the tumor cell death resistance upon chemotherapies. We are also deciphering the central roles of various types of programmed cell death in anti-tumor immunity, auto-immune diseases, and transplantation. We will reprogram cell death to modulate the immune response.
Understanding how extracellular signals are linked to gene expression is a fundamental challenge in biology, and more specifically, macrophage signal integration is central to understanding healthy versus aberrant regulation of inflammation. My laboratory uses quantitative approaches to address these problems, with major projects including (1) computational modeling of signaling-to-transcription in macrophages, (2) interrogating tissue-specific macrophage signaling, and (3) dissecting molecular determinants of macrophage inflammatory function. We use both data-driven and mechanistic modeling approaches to integrate transcription factor activity, global phosphorylation, and transcriptomic data to explore signaling mechanisms that shape macrophage function. In the tissue context, we use a combination of network-based approaches and hypothesis driven in vivo experiments to identify mechanisms linking tissue stimuli (e.g. cytokines and lipids) to transcription factor activity, and ultimately macrophage function. We hope these efforts will yield insights into dysregulation of signaling and inflammation, while informing therapeutic strategies.
The laboratory of Timothy Hand, PhD, is interested in the immune cells of the intestine and how they respond to the first interactions with colonizing microorganisms. How the immune system deals with newly colonizing bacteria is important, since too little immune response can lead to infection but too much can contribute to damaging inflammation. The intestine is home to the largest and densest group of microorganisms in the body and the intestinal microbiome is required for many host processes, most notably the digestion of complex carbohydrates. Therefore, maintaining a healthy relationship with the microbiome is important for the health of the host. Shifts in the intestinal microbiota and the mucosal immune response have been associated with a variety of important pediatric diseases including colorectal cancer, inflammatory bowel disease and necrotizing enterocolitis.
Our view is that the long- term relationship between the host and the microbiome can be shaped by the results of their initial interaction by the phenomenon of immunological memory. Therefore, we seek to better understand the immune systems ‘first impressions’ of the microbiota and how they are shaped by environmental factors such as diet and inflammation. Our hope is that a better understanding of how the microbiome shapes the host will lead to better therapies for pediatric disease. We also hope to harness this knowledge to improve our ability to use the immune response for therapy and augment anti-tumor immunotherapy.
The Hinterleitner Lab studies mucosal immune responses to gut microbes. Current projects are centered around how gut protists shape immune responses in the context of celiac disease, IBD, and colon cancer.
Bone marrow stem cell transplantation is, for many, the only curative treatment for leukemia and lymphoma-blood cancers. From this technique, we have learned that immune cells of the donor which are transferred in the transplant can eradicate blood cancer, in the so-called graft-versus-leukemia (GVL) effect. My research work is directed to finding ways to harness this GVL immune effect to cure leukemia and lymphoma. I am particularly interested in preventing and treating post-transplant relapse which remains the major cause of transplant failure. This involves two approaches: The first is to improve the results of transplants for people with leukemia by increasing the GVL effect and decreasing the hazards of the transplant through biomarker-directed personalized medicine and adoptive cellular immunotherapy. The second is to find ways to create a new immunotherapy boosting the patient's own immune system and thus avoid the complication of transplantation altogether.
As Director of the Solid Tumor Cell Therapy Program at UPMC Hillman Cancer Center, I oversee both clinical and research studies aimed at developing effective T cell-based immunotherapies for advanced cancer. We employ an integrated translational approach based upon preclinical in vitroexperimentation, in vivo murine models, and informative human clinical trials. The analysis of clinical results feeds further basic experimentation in an iterative process aimed at elucidating important immunologic principles for the successful treatment of human cancers.
My lab is currently pursuing several projects:
1. The role of TIM-3 in CD8+ T cells
This project currently involves the study of - TIM-3, a novel protein of the T cell immunoglobulin and mucin domain family in regulation of CD8+ T cell function during viral infection (using LCMV as a model system) and responses to syngeneic tumors. We are also interested in elucidating signaling pathways downstream of TIM-3.
2. The role of TIM-3 in regulatory T cells (Treg)
Work from our lab and others has shown that expression of TIM-3 is associated with acquisition of a more potent "effector" Treg (eTreg) phenotype. We are studying how this phenotype contributes to the effects of Treg on immune responses to viral infection and tumors, using both mouse models and correlative studies in humans.
3. Regulation of T cell and mast cell activation by PIK3IP1/TrIP, a novel regulator of PI3K
Dr. Kane's lab has found that a novel transmembrane protein known as PIK3IP1 (PI3K-interacting protein 1) or TrIP (transmembrane inhibitor of PI3K) is expressed in both T cells and mast cells. This protein appears to restrict early activation of both cell types. The lab is currently characterizing mice with inducible deletion of TrIP to better understand how this protein functions in vivo, especially in the context of syngeneic tumors.
Dr. Kirkwood’s research focuses upon melanoma immunobiology, therapy and prevention. His translational studies established the first effective adjuvant therapy of melanoma, and identified the immunological basis of this therapy, and are now probing the role of molecularly targeted agents (BRAF, MEK, and PI3Kdelta/gamma inhibitors) that may improve upon the efficacy of anti-PD1 immunotherapy, both in advanced melanoma and in the adjuvant operable high-risk melanoma settings. He has advanced the multimodal therapy of melanoma with surgery, stereotactic radiotherapy, and molecular antitumor agents, displacing chemotherapy in the management of melanoma. He is now pioneering novel clinical trial designs to assess the myriad potential combinations of recently-approved molecular and immunological therapies that are anticipated to be the focus of translational clinical research trials in melanoma for the next decade.
His laboratory is engaged in the molecular and immunohistological analysis of tissues obtained from local institutional, regional, national, and international trials of new therapy. Tumor tissues from patients participating in new modalities and combination therapies, neoadjuvant trials, and prevention interventions are probed using current immunopathological and molecular assessments of signaling pathways, and immune responses to melanoma. Dr. Kirkwood initiated the Biospecimen Repository of the Melanoma and Skin Cancer Program (1996-present, 7,000+ specimens) funded initially through his Specialized Program of Research Excellence 2008-2019, and more recently an endowment that have been promoted research by investigators within and outside the University of Pittsburgh, the Regional Melanoma Translational Research Consortium, the National Clinical Trials Network and the International Melanoma Working Group.
Dr. Lotze's primary area of research is broadly in tumor immunology, particularly the role of cellular therapy using dendritic cells, T cells, and NK cells. His current research interests include the further identification of clinical biomarkers and surrogates in the setting of cancer, the role of cell death pathways and autophagy, the nuclear protein high molecular group B1 [HMGB1] and other Damage Associated Molecular Pattern Molecules [DAMPs] in tissue injury, repair, and cancer. He is currently preparing major reviews on the role of costimulation as part of the therapeutic approach to cancer, integrating cancer biology and tumor immunology.
Jason J. Luke, MD, FACP, is an Associate Professor of Medicine at the University of Pittsburgh and UPMC Hillman Cancer Center where he is Associate Director for Clinical Research and the Director of the Immunotherapy and Drug Development Center (Phase I). Dr. Luke specializes in early phase drug development for solid tumors (particularly novel immunotherapeutics and biomarkers of immunotherapy activity) as well as the management of melanoma.
Dr. Luke is one of the foremost international investigators in the realm of immuno-oncology, having led clinical trials of immunotherapies including but not limited to anti-PD1/L1, CTLA4, many secondary checkpoints, bispecific approaches (checkpoint, CD3 and cytokine), metabolism modifiers (IDO, A2Ar/CD73/CD39 and arginase), innate agonists of STING, TLRs and oncolytic virus as well as solid tumor cellular therapies (TCRs and CART). In melanoma, Dr. Luke has designed and led two practice changing trials determining the role of anti-PD1 + CTLA4 after initial anti-PD1 failure (compendium listed in the NCCN) and altering the landscape of melanoma oncology practice across dermatology, surgery and medical oncology via establishment of modern adjuvant therapy with anti-PD1 for node negative stage IIB/C disease (leading to FDA/EMA approval). Dr. Luke has been a major contributor toward the investigation of radiation and the microbiome in relation to cancer immunotherapy. Dr. Luke’s major translational research focus leverages large scale informatics to advance cancer immunotherapy.
Dr. Luke received his MD from Rosalind Franklin University of Medicine and Science in Chicago. He then pursued internship and residency at the Boston University Medical Center followed by medicine and medical oncology fellowships at Weill Cornell Medical College and Memorial Sloan-Kettering Cancer Center in New York City. Following fellowship, Dr. Luke was a tenure-track, Type 1 Instructor in Medicine at Harvard Medical School as well as Staff Physician at the Dana-Farber Cancer Institute and Brigham and Women’s Hospital in Boston. Thereafter Dr. Luke was an Assistant Professor at the University of Chicago.
Dr. Luke is currently Senior Editor at Clinical Cancer Research, Section Editor at the Journal for Immunotherapy of Cancer and Skin Cancer Section Editor for the American Cancer Society journal Cancer. Dr. Luke is actively involved in several professional societies including SITC (where he sits on the Board of Directors), AACR, ASCO, and the Society for Melanoma Research, having served on the scientific program committees for each. Dr. Luke leads an R01 funded laboratory, he is co-PI for the Pittsburgh UM1 LAO and is project 3 clinical co-leader of the Pittsburgh Skin Cancer P50 SPORE, in addition to multiple private and state awards. Dr. Luke has received several awards for research and clinical care including the Melanoma Research Foundation Humanitarian Award, Crain’s 40 under 40, DOD Career Development Award, Paul Calabresi Career Development in Clinical Oncology Award (K12), ASCO Merit Award as well as Young Investigator Awards from the Melanoma Research Alliance, the Cancer Research Foundation and the Conquer Cancer Foundation of ASCO.
Our lab is exploring the role of the gut and tissue microbiome on systemic immunity in the context of complex diseases such as autoimmunity and cancer. Further we ask how we can use other environmental factors such as physical exercise and diet to tune microbiota metabolic output to modulate systemic immunity thereby changing cancer outcome.
Yana G. Najjar, MD is a translational investigator and cutaneous oncologist at the UPMC Hillman Cancer Center, where she is an Assistant Professor of Medicine and Director of the Clinical and Translational Research Center. Dr. Najjar specializes in the treatment of advanced melanoma, focusing on anti-PD1 resistant melanoma and rare melanoma subtypes. Using a bench-to-bedside approach, she has developed multiple investigator-initiated trials that aim to remodel melanoma tumor cell metabolism and hypoxia in the tumor microenvironment to overcome mechanisms of resistance to immunotherapy. Her lab is focused on various correlative analyses from investigator-initiated trials. Dr. Najjar's research is funded by the NIH, the Department of Defense and the Melanoma Research Alliance.
Prior to joining the faculty of the Department of Neurological Surgery at the University of Pittsburgh in 1992, Dr. Ian Pollack was awarded the 1991 Van Wagenen Traveling Fellowship, which afforded him a year of subspecialty training in the Department of Neurosurgery at the Hospital for Sick Children in Toronto, the Neuro-Oncology Laboratory of the University of Lausanne in Switzerland, and the Laboratory of Tumor Biology of the University of Uppsala in Sweden. Dr. Pollack graduated magna cum laude from Emory University in 1980, where he earned a BS degree in chemistry. He received his medical degree from the Johns Hopkins University School of Medicine in 1984, then completed a surgical internship and neurosurgical residency at the University of Pittsburgh School of Medicine. Dr. Pollack has published more than 400 papers in refereed journals, numerous book chapters and invited papers, and has edited two books on childhood brain tumors. He is co-editor of the recently published book Principles and Practice of Pediatric Neurosurgery and an accompanying atlas Operative Techniques In Pediatric Neurosurgery. He is currently a principal investigator on numerous NIH and foundation grants focusing on novel therapies for brain tumors and evaluating molecular markers of tumor resistance to therapy. He chaired the CNS Tumor Committee of the Children's Oncology Group from 2000 to 2009, co-chaired the National Cancer Institute Brain Malignancy Steering Committee from 2010-2017, is on the Executive Committee of the NCI-Funded Pediatric Brain Tumor Consortium, and is the immediate Past-Chair of the American Board of Pediatric Neurosurgery.
Our research program focuses on the mechanisms of cellular and molecular interactions in the tumor microenvironment. The elements of the tumor microenvironment can collectively exert both stimulatory and inhibitory pressures on the proliferative, angiogenic, neurogenic and immunomodulating potential of cancerous cells, as well as their ability to spread and metastasize. Thus, insights into the mechanisms regulating host responses to growing tumors are essential for assessing relative risks and improving the therapeutic index for novel therapies associated with the modulation of the tumor microenvironment. Tumor-mediated immune suppression and tolerance remains a key obstacle to the safe and efficacious induction of antitumor immunity by immunotherapeutic modalities. Tumor innervation by afferent and efferent branches of the Peripheral Nervous System and intratumoral neuronal and neuroglial elements are responsible for attraction and activation of immune regulatory cells and for direct regulation of malignant cell proliferation, spreading and metastasis. Cytokines, chemokines, and regulatory RNAs derived from the neuroglial cells play the major role in this phenomenon. Our long-term goal is to develop a feasible and effective therapeutic approach based on a combination of pharmacological inhibition of specific MRC pathways and recovery/boosting of tumor specific immune responses.
My laboratory studies tumor immunobiology and designs immunotherapies for the treatment of cancer based on results from translational modeling. My near-term research goal remains the development of novel phase I/II clinical trials for the treatment of patients with cancer, with a focus on melanoma and renal cell carcinoma (RCC). Such treatment modalities include dendritic cell (DC)-based vaccines, cytokine gene-modified DC injected directly into tumor lesions and combination treatment approaches integrating agents that modulate tumor cell immune recognition and/or alter the balance or Type-1 versus regulatory immunity in the tumor microenvironment (TME). We discovered that immune targeting of the tumor-associated vasculature occurs naturally during effective immunotherapy, and that vaccines targeting tumor blood vessel antigens (TBVA) can promote tumor regression, even in cases where cancer cells themselves cannot be directly recognized by protective/therapeutic CD8+ T cells. Notably, even though these vaccines target normal non-mutated peptide sequences in TBVA proteins, no untoward (auto)immune-related pathology was observed in translational mouse modeling. We determined that treatment with anti-angiogenic agents leads to tumor vascular normalization and to the improved chemokine-dependent recruitment of therapeutic T cells into the TME, resulting in local formation of tertiary lymphoid structures (TLS) in association with slowed tumor growth and extended survival in animal models. We recently completed a pilot phase II clinical trial (UPCI 12-048/NCT01876212) evaluating combined treatment of HLA-A2+ patients with autologous aDC1/TBVA peptide vaccines + dasatinib (employed as an immune adjuvant). Vaccines were well tolerated by patients and we observed objective clinical responses in 46% of evaluable patients with advanced-stage cutaneous or uveal melanoma, including 57% of patients with prior demonstration of primary resistance to anti-PD1-based immunotherapy. Novel DC/TBVA peptide vaccines are currently being investigated in pilot phase II studies supported by NIH R01 (NCT05127824) and P01 (NCT04093323) in the setting of checkpoint-refractory advanced melanoma and early-stage renal cell carcinoma. We are also currently investigating the use of IRF3 agonists (including STING agonists) delivered directly into the TME as components of in situ vaccines in the advanced disease setting with the intent to promote formation of TLS in situ for improved local cross-priming of novel therapeutic anti-tumor B cell and T cell repertoires.
Our research focuses on various aspects of T cell regulation and function:
(1) Mechanistic Focus:
(a) Immune Regulation: Regulatory T cells (Tregs): Identification of novel Treg molecules and their function; mechanism of Treg function; regulation of Treg stability via Nrp1 and other pathways; IL-35 signaling and mechanism of action; novel Ebi3 binding partner; IL-10 & IFNy function; neuron-immune interactions.
(b) Immune Regulation: Inhibitory Molecules: Identification of novel inhibitory receptors (IR) and their mechanisms; immune modulation of T cell subsets by LAG3; PD1 and NRP1; PD1-LAG3 synergy; mechanism of CD8+ and CD4_ T cell exhaustion; protein engineering to develop novel therapeutics.
(c) Structure-function analysis of T cell receptor (TCR):CD3 complex and LAG3 signaling: Mechanism of TCR:CD3 signaling; modulation & control of TCR signaling by IRs.
(d) Systems Immunology: Single cell systems approaches (transcriptomic & epigenomic) to hypothesis test, hypthesis generate and discover; technology and algorithm development; multispectral imaging.
(2) Disease Focus:
(a) Cancer: Biology of LAG3/PD1, IL-35 and NRP1 in mouse models of cancer and also in samples from treatment-naive patients or immunotherapy recipients; primary focus on solid tumors – head & neck, melanoma, lung, ovarian, breast cancer, with some work on pancreatic, GI and glioma cancers, and pediatric solid malignancies; novel approaches for therapeutic translation; biomarker discovery.
(b) Autoimmune and Inflammatory Disease: Impact, function & insufficiency of Tregs and IRs in several autoimmune and inflammatory disease with emphasis on models of autoimmune diabetes (NOD), EAE and asthma; development of therapeutic approaches (enhance Treg stability; IR agonists.
Dr. Whiteside’s research interests are in tumor Immunology and immunotherapy with special focus on mechanisms of tumor-induced immunosuppression, extracellular vesicles, cytokine networks, immunology of human head and neck cancer, melanoma, acute myelogenous leukemia and breast cancer. Her research is focused on mechanisms of tumor escape from the host immune system and the development of therapies designed to eliminate tumor escape. She studies the role of check point inhibitors in cancer progression. Currently she is investigating contributions tumor derived small extracellular vesicles or exosomes (TEX) to promotion of cancer progression. Specifically, mechanisms of TEX-induced apoptosis of CD8+ effector T cells and activation of regulatory T cells are investigated. Also, studies are evaluating the potential of TEX in the body fluids of cancer patients to serve as “liquid cancer biopsy” in predicting cancer progression, response to therapy and survival. Studies of TEX as well as subsets of EVs produced by immune cells in re-programming of the tumor microenvironment are performed using human specimens and mouse models of tumor growth.
Hassane Zarour, MD is a dermatologist and cancer immunologist whose research focuses on basic and translational human cancer immunology in the melanoma field. His work has led to the identification of novel melanoma MHC class II-presented epitopes that have been used in investigator-initiated trials at UPMC Hillman Cancer Center as well as in multi-center trials. Most recently, Dr. Zarour's work has contributed to elucidating the role of inhibitory receptors in promoting melanoma-induced T cell dysfunction in the tumor microenvironment. These findings led to the development of novel antibodies targeting inhibitory receptors for clinical trials. Dr. Zarour actively contributes to the design and the implementation of novel investigator-initiated trials based on laboratory findings, including two melanoma vaccine trials funded by the Cancer Research Institute and the National Cancer Institute, respectively. He is the lead scientific investigator on the Hillman Skin Cancer SPORE Project 3 that is testing the novel combination of BRAF inhibitor (BRAFi) therapy with high-dose interferon for metastatic V600E positive melanoma. He is also testing a novel combination of an anti-PD-1 antibody (MK 3475/Pembrolizumab) and PEG-interferon with grant support from an academic-industry award of the Melanoma Research Alliance.
