Friday, April 19, 2024
4/19/2024
Project Summary Acute Myeloid leukemia (AML) has a median survival of only six months in relapsed elderly patients. For this reason, there is great interest in developing targeted therapeutics to improve efficacy while decreasing morbidity. Recent reports of chimeric antigen receptor (CAR) T cells targeting antigens expressed on acute and chronic lymphocytic leukemia shed light on novel immune-based approaches for relapsed and/or refractory hematological malignancies. However, CAR T cells have not yet been successful in treating AML in the clinic due to the lack of an ideal target, as some reported targets (e.g., CD123 and CD33) deplete hematopoietic stem cells and/or myeloid cells. In contrast, our preliminary data showed that targeting FLT3 with CAR T cells is relatively safer because FLT3-CAR T cells do not kill healthy peripheral blood mononuclear cells in vitro and do not significantly affect self-renewal and repopulation of hematopoietic stem cells. Thus, we believe FLT3 is a relatively better target for CAR T cells in the treatment of AML. We therefore generated CAR T cells targeting FLT3. FLT3-CAR T cells enhance in vitro eradication of AML blasts isolated from patients and eliminate human AML cells engrafted into immunodeficient mice. T cells (including CAR T cells) can become exhausted and suppress immune responses when fighting tumor cells in the tumor microenvironment. This is at least partially due to the increased expression of the PD-1 receptor, a key checkpoint inhibitor modulating T cell activation. The anti-PD-1 T cell checkpoint blockade antibody is designed to reverse T cell exhaustion and has shown promising clinical efficacy for the treatment of various cancers. Our group and others have previously demonstrated that PD-1 is also expressed on NK cells in cancer patients but not in resting NK cells. Thus, it is more effective to combine CAR T cells and PD-1 checkpoint blockade to enhance the power of both NK cells and T cells. In this study, we added a frame to the FLT3 CAR construct that we have generated to express anti-PD-1 single chain antibodies (scFvPD1). We have engineered T cells with this construct to generate so-called scFvPD1-FLT3 CAR T cells that are able to target FLT3 in AML using FLT3-CAR T cells simultaneously expressing soluble scFvPD1 to restore the function of exhausted T cells. CAR T cells and patient NK cells also express inhibitory PD-1. Thus, the soluble scFvPD1 produced by scFvPD1-FLT3 CAR T cells will further augment the antitumor activity of FLT3-CAR T cells in an autocrine manner, and endogenous NK and T cells in a paracrine manner. With this multipronged attack to augment immune responses against tumor cells, we believe our approach has the potential to successfully treat relapsed and/or refractory AML. We have three Aims proposed to test scFvPD1-FLT3 CAR T cells in vitro and in vivo: Aim 1, further in vitro testing of scFvPD1-FLT3 CAR T cells; Aim 2, In vivo preclinical testing of scFvPD1- FLT3 CAR T cell efficacy; Aim 3, Combination therapy using scFvPD1-FLT3 CAR T cells and midostaurin, a drug recently approved by the U.S. FDA, which we have found induces FLT3 surface expression on AML blasts.
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