DEPLETION REGIMES FOR ENGINEERED T-CELL OR NK-CELL THERAPY
The invention provides method of depleting endogenous T-cells or NK-cells to facilitate propagation or survival of engineered T-cells introduced into a subject for a therapeutic purpose. The depletion regime involves a co-administration of an immunotherapeutic agent against T-cells and an immunotherapeutic agent that inhibits CD47 interaction with NK-cells. The immunotherapeutic agent against T-cells or NK-cells binds to an antigen on T-cells or NK-cells effecting depletion of the T-cells or NK-cells, which depletion is promoted by the immunotherapeutic agent inhibiting CD47-SIRPα interaction. The genetically engineered T-cells or NK-cells can have a variety of genetic modifications such as a chimeric antigen receptor that targets the T-cells to a target cell.
1 . A method of performing T-cell or NK cell therapy in a subject in need thereof, comprising:
administering to the subject a combination therapy comprising an immunotherapeutic agent antagonizing CD47 interaction with SIRPα and an immunotherapeutic agent binding to a T-cell or NK cell antigen, thereby depleting endogenous T-cells or NK-cells of the subject, wherein the subject is also administered genetically engineered T-cells or NK-cells.
2 . The method of claim 1 , wherein the subject is administered the genetically engineered T-cells.
3 . The method of claim 2 , wherein the T-cell are genetically engineered to have a chimeric antigen receptor.
4 . The method of claim 3 , wherein the chimeric antigen receptor, comprises an scFv or Fab, a transmembrane domain and an intracellular signaling domain.
5 . The method of claim 3 , wherein the chimeric antigen receptor comprises a CD16 extracellular domain, a transmembrane domain and an intracellular signaling domain, wherein the CD16 domain is complexed with an Fc domain of an antibody.
6 . The method of claim 2 , wherein the genetically engineered T-cells are genetically engineered to express alpha and beta domains of a T-cell receptor.
7 . The method of claim 1 , wherein the genetically engineered NK-cells are administered.
8 . The method of any preceding claim, wherein the immunotherapeutic agent antagonizing CD47 interaction with SIRPα is an antibody specifically binding to CD47.
9 . The method of claim 8 , wherein the antibody is magrolimab.
10 . The method of claim 8 or 9 , wherein the antibody specifically binding to CD47 is administered at a priming dose followed by a higher therapeutic dose.
11 . The method of any one of claims 1 - 8 , wherein the immunotherapeutic agent antagonizing CD47 interaction with SIRPα is an antibody specifically binding to SIRPα.
12 . The method of claim 11 , wherein the antibody comprises a heavy chain variable region having a sequence comprising SEQ ID NO:19 and a light chain variable region having a sequence comprising SEQ ID NO:20.
13 . The method of claim 11 , wherein the antibody specifically binding to SIRPα is any of FSI-189, ES-004, BI765063, ADU1805, and CC-95251.
14 . The method of any preceding claim, wherein the immunotherapeutic agent antagonizing CD47 interaction with SIRPα is administered at a dose of 10-30 mg/kg.
15 . The method of any one of claims 11 - 14 , wherein a single dose of the antibody specifically biding to SIRPα is administered.
16 . The method of any one of claims 11 - 14 , wherein two or more doses of the antibody specifically binding to SIRPα are administered.
17 . The method of any preceding claim, wherein the immunotherapeutic agent specifically binding to a T-cell antigen specifically binds to CD2, CD3, CD4, CD8, CD52, CD45 or ATG.
18 . The method of any preceding claim, wherein the T-cells administered to the subject are autologous T-cells.
19 . The method of any one of claims 1 - 17 , wherein the T-cells administered to the subject are allogenic T-cells.
20 . The method of any one of claims 1 - 17 , wherein the T-cells administered to the subject have a T-cell receptor linked to an antibody against a cancer-associated antigen.
21 . The method of any preceding claim, wherein the subject has a cancer expressing a cancer-associated antigen and the T-cells or NK-cells are engineered to bind to the antigen.
22 . The method of any preceding claim, wherein the combination therapy is performed before the subject is administered the T-cells or NK-cells.
23 . The method of any preceding claim, wherein the T-cells or NK cells administered to the subject are engineered for reduced binding to the immunotherapeutic agent specifically binding to the T-cell or NK cell antigen and/or the immunotherapeutic agent antagonizing CD47 interaction with SIRPα.
24 . The method of any preceding claim, wherein the combination therapy does not include an antibody specifically binding to c-kit.
25 . The method of any preceding claim, wherein the combination therapy does not include a genotoxic or myeloablative agent.
26 . The method of any preceding claim, wherein the combination therapy does not include dimethyl busulfan.
27 . The method of any preceding claim, wherein the subject has a cancer.
28 . The method of claim 27 , wherein the cancer is a leukemia, lymphoma, myeloma or myelodysplastic syndrome.
29 . The method of claim 27 , wherein the cancer is a hematological cancer.
30 . The method of claim 27 , wherein the cancer is a solid tumor.
31 . The method of any one of claims 27 - 30 , further comprising administering a second agent to treat the cancer.
32 . The method of claim 30 , wherein the subject is administered the second agent the before or during depletion of the T-cells or NK cells.
33 . The method of claim 31 or 32 , wherein the agent is a chemotherapeutic agent, anti-angiogenic agent, anti-fibrotic agent or monoclonal antibody against a cancer antigen.
34 . The method of any preceding claim further comprising administering a flt3 agonist or CISH inhibitor after depletion of the T-cells or NK-cells to promote growth of the engineered T-cells or NK cells.
35 . The method of any preceding claim further comprising administering an MCL1 inhibitor with the immunotherapeutic agent antagonizing CD47 interaction with SIRPα to increase depletion of NK cells.
36 . The method of any preceding claim, wherein the patient is a human.
37 . Use of an immunotherapeutic agent antagonizing CD47 interaction with SIRPα in the manufacture of a medicament for depleting endogenous T-cells or NK-cells before administration of genetically engineered T-cells or NK-cells in combination with an immunotherapeutic agent binding to a T-cell or NK cell antigen.
38 . Use of immunotherapeutic agent binding to a T-cell or NK cell antigen in the manufacture of a medicament for depleting endogenous T-cells or NK-cells before administration of genetically engineered T-cells or NK-cells in combination with an immunotherapeutic agent antagonizing CD47 interaction with SIRPα.
39 . The use of claim 37 or 38 in accordance with the method of any of claims 2 - 36 .