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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.
Dr. Bailey studies pediatric sarcoma biology. Currently, her specific focus is studying the impact of the EWS-FLI1 fusion oncoprotein on the Ewing sarcoma tumor microenvironment.
Our research interests are focused on the mechanisms of cross-priming of antigens during immune responses to cancer, viruses and autoimmunity. The pursuit of this research area stems from the observations that in many situations, heat shock proteins (HSPs) are both necessary and sufficient for cross-presentation. HSPs are adept at this because of several unique properties, including their ability to:
HSPs thus elicit remarkable immune responses specific for the peptides they chaperone. The laboratory is using these observations to examine new facets of antigen presentation and also to develop novel immunotherapies for cancer, infectious disease and autoimmune disorders.
A related area of research examines how other ligands for the HSP receptor CD91 interact with the immune system. In the past few years, we have shown that a2-macroglobulin (a2M), a CD91 ligand, though not a bonafide HSP, shares the immunogenic properties of HSPs and can elicit immune responses specific to (peptide) substrates that it chaperones. We are currently exploring the identification of naturally formed a2M-substrate complexes and the potential use of these immunogenic complexes as therapeutic agents for cancer and infectious disease.
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.
Dr. Edwards' research interests include cervical and ovarian malignancies. He serves as principle investigator of the Gynecologic Oncology Group for the University of Pittsburgh and 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.
Dr. Ferris's laboratory is focused on understanding basic immunological mechanisms of the T lymphocyte response to cancer, for the development of novel immunotherapeutic approaches to head and neck cancers (HNC). Tumor vaccine clinical trials are currently underway and new strategies are in development. We are particularly interested in the immune response to human papillomavirus (HPV)-associated head and neck cancer, which appears to be a distinct subgroup of head and neck squamous cell carcinomas. Monitoring the successful immune effects of individuals treated with immunotherapy is a major effort, in order to develop improved generations of vaccine approaches. We are also studying tumor induced immune evasion, such as defective antigen processing and presentation to subvert cytotoxic T lymphocyte recognition of tumors.
Another area of study involves the promotion of tumor metastasis by a family of molecules called chemokines. We are finding important roles for chemokine receptors in cancer metastasis. These chemokines are small, secreted molecules that mediate homing and recruitment of immune cells in response to inflammation, through a family of G-protein linked receptors. Overall, these studies are designed to identify the chemokines relevant to progression of HNC and to provide initial data on their possible clinical utility as components of future vaccination therapies for HNC. In addition, our group is interested in developing immune/inflammatory biomarkers present in the bloodstream for HNC detection, and monitoring in populations at risk for cancer recurrence and/or second primary tumors.
My lab is focused on the study of signal transduction pathways that regulate antigen-dependent activation of T cells and mast cells. Toward that end, we are engaged in several specific projects: 1. Understanding the signaling pathways downstream of Carma1, MALT1 and Bcl10 (CBM complex) in T cells 2. Defining biochemical and spatial regulation of NF-kB activation by the TCR/CD3 complex, along with CD28 co-stimulation 3. Understanding signal transduction pathways downstream of the transmembrane proteins Tim-1 and Tim-3, in T cells and mast cells
The Kirkwood laboratory is engaged in the study of melanoma immunobiology, and the assessment of multiple new immunomodulators in the context of trials conducted by the Hillman Melanoma Program, and the SPORE in Melanoma and Skin Cancer, as well as the International Melanoma Working Group. The study of predictive and prognostic biomarkers of melanoma complements the studies of molecular inhibitors of melanoma signaling and immunomodulatory agents given alone and in combination with one another.
I aim to advance the treatment of melanoma by complementing clinical care with the principles of translational science. Specifically, my research focuses on immunotherapy in advanced melanoma and its impact on the tumor microenvironment and the peripheral immune system. My goal is to develop rational combinations of immunotherapy, targeted therapy and other agents that may potentially remodel the tumor microenvironment in order to render it less hostile to the host immune system.
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 250 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 grants focusing on novel therapies for brain tumors and evaluating molecular markers of tumor prognosis. He has co-chaired the National Cancer Institute Brain Malignancy Steering Committee since 2010.
Our laboratory research focuses on the study of tumor immunobiology and designing immunotherapies for the treatment of cancer. Our translational murine models and human in vitro studies are intended to serve as a foundation for the development of phase I/II clinical trials of modalities that can more effectively treat patients with melanoma or renal cell carcinoma. Such modalities include dendritic cell (DC)-based vaccines, cytokine gene-modified DC injected directly into tumor lesions, and combinational approaches integrating agents that modulate tumor cell immune recognition (i.e., HSP90 inhibitors) or alter the balance of Type-1 versus regulatory immunity in the tumor microenvironment (i.e., sunitinib). Most recently, we have discovered that immune targeting of the tumor-associated vasculature occurs naturally as a consequence of effective immunotherapy (via DC1-based cross-priming of T cells), and that vaccines based on tumor-associated blood antigens (TBVA) can promote tumor regression even in cases where cancer cells cannot be directly recognized by the protective CD8+ immune system. We have also determined that anti-angiogenic agents such as the tyrosine kinase inhibitors sunitinib, axitinib and dasatinib all lead to tumor vascular normalization and to the improved delivery of anti-TBVA T cells into the tumor microenvironment (TME) allowing for improved anti-tumor efficacy. This has most recently resulted in the development of our NIH-supported clinical trial UPCI 12-048 'A Randomized Phase II Pilot Study of Type I-Polarized Autologous Dendritic Cell Vaccines Incorporating Tumor Blood Vessel Antigen (TBVA)-Derived Peptides in Combination with Dasatinib in Patients with Metastatic Melanoma' (H. Tawbi, Clinical PI) that is currently accruing patients.
Proposing to identify immune biomarker discovery for disease management of endometriosis and ovarian cancer, the Vlad lab is investigating numerous questions about immune surveillance in women with these diseases. Via collaborations with our clinician colleagues at Magee-Womens Hospital of UPMC, the lab is working on implementing new clinical trials exploring the roles of novel immune biologics as adjuvant therapies in ovarian cancer.
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.