- Director, Center for Synthetic Immunity
Natural killer (NK) cells are an important part of the innate immune system and have the ability to kill tumor cells and some virus-infected cells while sparing nearby normal cells. Dr. Sentman's research interests are NK cell recognition mechanisms, the role of NK cells as a part of the immune defense against cancer and infection, and how NK cell and T cell effector mechanisms affect the tumor microenvironment. His laboratory is focused on the development of novel immunotherapy strategies for cancer, and there are several major areas of research: chimeric NK cell receptor based immunotherapy, bi-specific antibody targeting of tumors using NK cell receptors, and development of novel signaling platforms for cell based therapies.
NK receptor based chimeric antigen receptors (CARs) as immunotherapy: NK cells express a number of different receptors that can recognize tumor cells, and their ligands are expressed on many different types of tumor cells making them good targets for the treatment of cancer. Dr. Sentman's lab has developed a novel immunotherapy targeting strategy using chimeric NKG2D receptors. These NKG2D CARs are formed by a fusion of NKG2D with a cytoplasmic signaling domain of CD3zeta. However, because NKG2D is a type II protein, the orientation of CD3zeta is reversed. NKG2D recognizes several ligands that are often expressed on tumor cells but not normal tissues. Almost 90% of human cancers are of tumor types that have been shown to express ligands for NKG2D. In addition, immunosuppressive cells (MDSCs, Tregs) may also express NKG2D ligands within the tumor microenvironment. When expressed in T cells by viral transduction, these NKG2D CARs are able to recognize tumor cells in an MHC independent manner, and they trigger T cells to produce proinflammatory cytokines and kill tumor cells upon recognition of their ligands. In fact, extensive analysis in syngeneic lymphoma and ovarian cancer models has shown that both cytotoxicity and cytokines are an essential part of the CAR T cell efficacy. Dr. Sentman's laboratory is using this approach to target ovarian cancer, lymphoma, and myeloma, and this approach has the potential to be applied to other tumors such as breast cancer, melanoma, and osteosarcoma. His laboratory is working on development and analysis of a number of other CARs based on NK cell receptors and their ligands.
Bi-specific T cell engagers: It is possible to target tumors effectively using bi-specific antibodies that trigger T cell effector function when they also bind to ligand expressing tumor cells. Dr. Sentman's laboratory has developed a bi-specific T cell engager or BiTE based on the scFv from anti-CD3 and NKG2D. This hybrid molecule binds to T cells via CD3 and to tumor cells via NKG2D. These small bi-specific proteins lack a Fc receptor, which avoids off-tumor toxicity due to potential interaction with Fc receptor expressing cells such as macrophages or dendritic cells. Clinical data using an anti-CD19-anti-CD3 bi-specific molecule demonstrated excellent efficacy at very low doses. The potential of these bi-specific molecules is to treat cancer through activation of a patient's own T cells. Dr. Sentman's research group is developing novel bi-specific molecules based on various NK cell receptor and their ligands, demonstrating efficacy in melanoma and lymphoma models, and investigating their mechanisms of action against different tumor types.
Novel cell based therapies: Dr. Sentman's team is working on developing several new signaling platforms that can serve as the basis for adoptive cell therapies against cancer, autoimmunity, and infectious diseases. These platforms are designed to be used with many different recognition strategies to allow flexibility to create cell based therapies that bind to key targets and provide unique effector functions to modify local immunity.
Clinical development: Dr. Sentman is working in collaboration with Celdara Medical LLC and the Dana-Farber Cancer Center to move the NKG2D-based CAR into a Phase I clinical trial. He is also working with clinicians at Dartmouth-Hitchcock Medical Center and other collaborators to develop and move their other therapeutic ideas into clinical development. Several of these technologies have been patented or have patents pending. To inquire about licensing or collaborative opportunities, please contact Dr. Sentman or the Dartmouth Technology Transfer Office.
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