Therapeutic targeting of tumor escape by car-mediated trogocytosis
AssigneeUniversity of Maryland, Baltimore
InventorsTim LUETKENS, Kenneth A. DIETZE
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Abstract
Populations of CAR T cells that exhibit reduced trogocytosis are disclosed, as well as methods for making such cells and methods of using such cells in the treatment of cancer. A reduction in trogocytosis is achieved by inhibiting Cathepsin B in the CAR T cells and/or inducing ubiquitylation of cancer antigens taken up by the CAR T cells.
Claims49
A population of chimeric antigen receptor (CAR) expressing T cells (CAR T cells) that exhibits reduced trogocytosis, wherein the CAR T cells express or overexpress an inhibitor of Cathepsin B.
A population of CAR T cells that exhibits reduced surface expression of cancer antigens, wherein the CAR T cells express or overexpress an effector of ubiquitylation.
A population of CAR T cells that exhibits both reduced trogocytosis and reduced surface expression of cancer antigens, wherein the CAR T cells express or overexpress an inhibitor of Cathepsin B and express or overexpress an effector of ubiquitylation
A method of treating cancer in a subject comprising (a) contacting a population of CAR T cells with a Cathepsin B inhibitor and (b) administering the cells of (a) to a subject having cancer.
A method of treating cancer in a subject comprising administering a Cathepsin B inhibitor and a population of CAR T cells to a subject having cancer.
A method of augmenting anti-cancer activity of CAR T cells in a subject comprising administering a Cathepsin B inhibitor to a subject undergoing CAR T cell therapy.
A method of inhibiting trogocytosis in CAR T cells in a subject comprising administering a Cathepsin B inhibitor to a subject undergoing CAR T cell therapy.
A method of treating cancer in a subject comprising administering a population of CAR T cells genetically modified to express or overexpress a Cathepsin B inhibitor to a subject having cancer.
A method of treating cancer in a subject comprising administering a population of CAR T cells genetically modified to express or overexpress an effector of ubiquitylation to a subject having cancer.
A method of treating cancer in a subject comprising administering a population of CAR T cells genetically modified to express or overexpress a Cathepsin B inhibitor and genetically modified to express or overexpress an effector of ubiquitylation to a subject having cancer.
A method of inhibiting trogocytosis in a population of CAR T cells comprising contacting the CAR T cells with a Cathepsin B inhibitor.
A method of decreasing trogocytosis in a population of CAR T cells comprising genetically modifying the population of CAR T cells to express or overexpress a Cathepsin B inhibitor.
A method of decreasing trogocytosis in a population of CAR T cells comprising genetically modifying the population of CAR T cells to express or overexpress an effector of ubiquitylation.
A method of decreasing trogocytosis in a population of CAR T cells comprising (i) genetically modifying the population of CAR T cells to express or overexpress a Cathepsin B inhibitor and (ii) genetically modifying the population of CAR T cells to express or overexpress an effector of ubiquitylation.
A method of generating trogocytosis-resistant CAR T cells comprising genetically modifying the population of CAR T cells to express or overexpress a Cathepsin B inhibitor.
A method of generating trogocytosis-resistant CAR T cells comprising genetically modifying the population of CAR T cells to express or overexpress an effector of ubiquitylation.
A method of generating trogocytosis-resistant CAR T cells comprising (i) genetically modifying the population of CAR T cells to express or overexpress a Cathepsin B inhibitor and (ii) genetically modifying the population of CAR T cells to express or overexpress an effector of ubiquitylation.
A method of decreasing surface expression of cancer antigens resulting from trogocytosis in a population of CAR T cells comprising genetically modifying the population of CAR T cells to express or overexpress an effector of ubiquitylation.
A method of targeted degradation of antigen transferred to CAR T cells via trogocytosis comprising genetically modifying the population of CAR T cells to express or overexpress an effector of ubiquitylation.
A method of assaying for inhibitors of trogocytosis, said method comprising:
- (a) genetically modifying a CAR T cell to express a N-terminal fragment of NanoLuc luciferase (nLuc),
- (b) genetically modifying a tumor cell to express a cancer antigen fused to a C-terminal NanoLuc fragment (cLuc),
- (c) culturing the cells of (a) and (b) in the presence of a selected inhibitor under conditions promoting trogocytosis, and
- (d) assaying the cells of (a) for luminescence.
Dependencies are inferred from the claim text.