A CD200R immunomodulatory fusion protein enhances T cell function and adoptive therapy targeting CD200+ leukemia cells
Shannon K. Oda1, Andrew W. Daman1, Nicolas M. Garcia1, Felecia Wagener1, Thomas M. Schmitt1, Xiaoxia Tan2, Aude G. Chapuis1, and Philip D. Greenberg1,2
1Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA; 2Department of Immunology, University of Washington, Seattle, WA
Acute myeloid leukemia (AML)—the most common adult acute leukemia in the U.S.—has the worst survival rate of leukemias, with only 26% of AML patients surviving 5 years. Adoptive immunotherapy, a promising treatment option, uses genetically modified T cells to recognize and eliminate tumors. However, the efficacy of T cell immunotherapy, particularly in the context of progressive leukemia, is dampened by limited costimulation as well as inhibitory signals interfering with T cell activation. CD200 (OX2), an immunosuppressive membrane protein commonly upregulated in leukemia and other malignancies, is associated with inhibited antitumor T cell responses and decreased patient survival. We engineered T cells with tumor-reactive T cell receptors and hypothesized we could improve the therapeutic efficacy by expressing a CD200 receptor(R)-CD28 immunomodulatory fusion protein (IFP) to replace CD200 inhibition with a costimulatory signal. Analysis of a panel of different sized CD200R-CD28 IFP constructs revealed tumor-T cell distance is critical for the ability of the complex to localize to the immunological synapse and achieve optimal costimulation. T cells transduced with the optimized CD200R-CD28 IFP exhibited enhanced proliferation and effector function in response to CD200+ target cells in vitro. In a model for adoptive therapy of disseminated leukemia, CD200R-CD28-transduced leukemia-specific T cells eradicated otherwise lethal disease more efficiently than wild type cells, and bypassed the requirement for IL-2 administration to sustain in vivo activity. Transduction of human primary T cells with the equivalent human IFP also increased proliferation and cytokine production in response to CD200+ leukemia cells, supporting clinical translation of this strategy.
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