Novel Approaches to the Design of Chimeric Antigen Receptors
While the mortality rate for many cancers has improved substantially, the prognosis remains poor for patients who present with advanced or recurrent disease. Current therapies, such as chemotherapy and radiotherapy, are highly toxic and the doses of these treatment modalities are often limited by their toxicity. The evolution of chimeric antigen receptor (CAR) technology offers great hope to patients who relapse. This optimism has been encouraged by the success of CTL019 in B cell leukemia. Unfortunately, the success seen in B-ALL has not yet been translated more broadly, especially in solid tumors. In addition, CARs have been associated with life-threatening toxicities, such as cytokine release syndrome and on-target/off-tumor effects. We developed a novel approach to CAR therapy that blends the antigen recognition capacity of traditional CARs with the functionality of the endogenous T cell receptor (TCR). The endogenous TCR complex is a large heteromeric structure that incorporates several mechanisms to regulate the kinetics and intensity of downstream signaling pathways. This regulation is critical for ensuring optimal differentiation of T cells.
Speaker: Tom Yankee, PharmD, PhD
Tom Yankee, PharmD, PhD is an Associate Professor of Microbiology, Molecular Genetics, and Immunology at the University of Kansas Medical Center. He also holds an appointment in the Division of Hematologic Malignancies and Cellular Therapeutics at the University of Kansas Medical Center. He also serves as the Scientific Director of the Flow Cytometry Core Laboratory. His research interests focus on applying an understanding of T cell biology to the field of immunotherapy. He has designed a novel chimeric antigen receptor platform for the treatment of cancer and is using innovative approaches to the suppression immune responses for graft-versus-host-disease. Dr. Yankee earned his PharmD degree from the University of Illinois at Chicago and his PhD from the Department of Medicinal Chemistry and Molecular Pharmacology at Purdue University. He then went to the University of Washington in Seattle and joined the Department of Immunology as a post-doctoral fellow.
Incorporation of NKG2D Signaling Into Cancer Immunotherapy
The immune system is capable of recognizing and destroying tumor cells. However, during cancer progression, immunoediting of tumor cells occurs and tumors escape from immune detection. The goal of immunotherapy is to reinstate immune-mediated destruction of cancer cells. The main cell types capable of direct tumor cell killing are cytotoxic T cells (CTL) and natural killer (NK) cells. For this killing to occur, these immune cells must express activating receptors that are stimulated by molecules present on the tumor cell surface. One of these receptors, which is expressed by all CTL and NK cells, is natural killer group 2, member D (NKG2D). Many nascent tumors of various types express NKG2D ligands, rendering them susceptible to CTL and NK cell lysis via NKG2D. However, NKG2D ligand expression is often lost with tumor progression. A long-term goal of our research is to determine whether methods to increase NKG2D signaling in immune cells are useful as a cancer immunotherapy strategy. I will first discuss our data supporting a role for NKG2D signaling in natural immunosurveillance of indolent B cell lymphomas. Next, I will describe our more recent data that illustrate a role for NKG2D signaling induced by NKG2D ligands expressed on CTL and NK cells in a mouse model of autoimmune diabetes and human cell culture, respectively. Finally I will discuss our future plans for testing the role of NKG2D ligand expression by CTL and NK cells, as well as incorporation of NKG2D signaling into CAR T cell therapy, in pre-clinical animal tumor models
Speaker: Mary Markiewicz, PhD
Mary Markiewicz, PhD, is an Assistant Professor in the Department of Microbiology, Molecular Genetics & Immunology at the University of Kansas Medical Center. She is a cellular immunologist with a strong interest in both tumor immunology and type 1 diabetes research. Dr. Markiewicz received her PhD in Immunology from the University of Chicago, where she performed tumor immunology studies. She continued her tumor immunology focus as a postdoctoral fellow for a year at Loyola University in Chicago. Dr. Markiewicz then moved to the Department of Pathology and Immunology at the Washington University School of Medicine in St. Louis and began her studies on the NKG2D immune receptor with a Postdoctoral Fellowship from the American Cancer Society. After completing her postdoctoral training, she became a Research Assistant Professor in the Department of Pathology and Immunology at Washington University School of Medicine. During this time, propelled by funding from the Diabetes Research Center at Washington University and a Junior Faculty Award from the American Diabetes Association, she began her studies investigating the role of NKG2D in autoimmune diabetes. With funding from the Molecular Regulation of Cell Development and Differentiation COBRE, Dr. Markiewicz joined the KUMC faculty in 2014.
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