Description

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. Greenberg^1,2

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.