A CD200R-CD28 fusion protein appropriates an inhibitory signal to enhance T-cell function and therapy of murine leukemia

Abstract

Acute myeloid leukemia (AML), the most common adult acute leukemia in the United States, has the poorest survival rate, with 26% of patients surviving 5 years. Adoptive immunotherapy with T cells genetically modified to recognize tumors is a promising and evolving treatment option. However, antitumor activity, particularly in the context of progressive leukemia, can be dampened both by limited costimulation and triggering of immunoregulatory checkpoints that attenuate T-cell responses. Expression of CD200 (OX2), a negative regulator of T-cell function that binds CD200 receptor (CD200R), is commonly increased in leukemia and other malignancies and is associated with poor prognosis in leukemia patients. To appropriate and redirect the inhibitory effects of CD200R signaling on transferred CD8 T cells, we engineered CD200R immunomodulatory fusion proteins (IFPs) with the cytoplasmic tail replaced by the signaling domain of the costimulatory receptor, CD28. An analysis of a panel of CD200R-CD28 IFP constructs revealed that the most effective costimulation was achieved in IFPs containing a dimerizing motif and a predicted tumor-T-cell distance that facilitates localization to the immunological synapse. T cells transduced with the optimized CD200R-CD28 IFPs exhibited enhanced proliferation and effector function in response to CD200 leukemic cells in vitro. In adoptive therapy of disseminated leukemia, CD200R-CD28-transduced leukemia-specific CD8 T cells eradicated otherwise lethal disease more efficiently than wild-type cells and bypassed the requirement for interleukin-2 administration to sustain in vivo activity. The transduction of human primary T cells with the equivalent human IFPs increased proliferation and cytokine production in response to CD200 leukemia cells, supporting clinical translation. This trial was registered at www.clinicaltrials.gov as #NCT01640301.

T-cells “à la CAR-T(e)” – Genetically engineering T-cell response against cancer

“…Further characterization of such kind of fusion (or natural CCR) should be explored. A recent report also depicted an extensive characterization and testing of different designs of human and murine CD200/CD28 CCR (or immunomodulatory fusion proteins -IFPs) [231].…”

Nsp1α of Porcine Reproductive and Respiratory Syndrome Virus Strain BB0907 Impairs the Function of Monocyte-Derived Dendritic Cells via the Release of Soluble CD83

“…During viral infection, MoDCs change cytokine secretion levels and alter the expression of major histocompatibility complex (MHC) proteins and costimulatory molecules on the cell surface (25,26). The MHC has a critical role in the immune response against viral infections, as MHC class I (MHC-I) molecules function in antigen presentation on the cell surface for T cell recognition (27)(28)(29). The MHC class I complex consists of three main subunit structures, which together enable the escape of immune proteins from the endoplasmic reticulum (ER) to the cell surface.…”

T-Cell Receptor–Based Immunotherapy for Hematologic Malignancies

“…101 Function of transferred T cells can also be increased by siRNA or CRISPR-Cas9 elimination of inhibitory molecule genes, such as programmed death protein-1, 102,103 or by converting negative malignant cellderived signals into activation signals for engineered T cells, for example, by fusing the inhibitory receptor CD200R to a costimulatory CD28 domain. 104 Normal signaling pathways, such as thrombopoietin and c-MPL, 105 can also be co-opted to deliver an activating signal to engineered T cells through the transgene construct. "Off-the-shelf " versions of engineered cells that are HLA-negative and express natural killer cell inhibitory molecules could be used as universal donor cells, 106 potentially eliminating the need for autologous cell collection from patients, although silencing the endogenous TCR will likely be required in this situation to prevent GVHD.…”