Overcoming cell therapy barriers in the suppressive tumor microenvironment with engineered proteins

C.E. Credits: P.A.C.E. CE Florida CE
Speaker
  • Assistant Professor | Department of Pediatrics, Division of Hematology/Oncology, University of Washington School of Medicine, Principal Investigator | Ben Towne Center for Childhood Cancer...
    Biography
      Dr. Shannon Oda earned a Ph.D. in Immunology from the University of Colorado Anschutz Medical Campus and completed her postdoctoral training with Dr. Philip Greenberg at the Fred Hutchinson Cancer Research Center. She has received several awards, including the Evergreen Fund Award and the LLS Career Development Program Special Fellow Award, and has been invited to give talks internationally. Dr. Oda joined the Seattle Children's Research Institute in 2020, where she is an Assistant Professor at the Ben Towne Center for Childhood Cancer Research and the University of Washington School of Medicine. Her research focuses on improving T cell immunotherapy, which uses immune cells to target and destroy cancer cells. She has identified several obstacles that inhibit immune cells from effectively eradicating tumor and she is inventing new ways to engineer T cells to overcome these obstacles and improve immunotherapy of hematological and solid tumors.

    Abstract

    Adoptive cell immunotherapy (ACT) with genetically-modified T cells has shown impressive efficacy against some cancers, particularly CD19+ leukemias. However, ACT efficacy in solid tumors can be limited by restrictive tumor microenvironments (TMEs), with increased inhibitory signals, reduced T cell infiltration/accumulation, and inadequate metabolic substrates. FasL is a death receptor ligand that is overexpressed in the majority of human TMEs and can protect tumor cells from immunity. To overcome this particular barrier, engineered immunomodulatory fusion proteins (IFPs), combining the Fas receptor ectodomain with the 4-1BB costimulatory signaling domain, thereby converting a negative signal into a positive one. T cells engineered with the Fas-4-1BB IFP exhibited enhanced proliferation and anti-tumor function, and reduced exhaustion in vitro. Fas-4-1BB T cells displayed characteristics consistent with 4-1BB signaling, including altered metabolism, increased mitochondrial density, and expression of pro-survival signaling molecules. In vivo, Fas-4-1BB T cells exhibited improved persistence and eradicated lethal murine leukemia. In the autochthonous KPC pancreatic tumor model, IFP ACT resulted in increased T cell accumulation in the tumor and significantly improved survival. The Fas-4-1BB IFP also enhanced primary human T cell expansion and anti-tumor function in vitro, supporting clinical translation.

    Learning Objectives:

    1. Identify 3 barriers to immune cell response to cancer

    2. List 3 approaches to overcome immunosuppressive barriers to bolster the immune response to cancer

    3. Explain how fusion proteins can convert a negative signal to a positive boost for T cells


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