Use of CD33CAR modified high affinity NK cells (t-haNK) to reduce myeloid-derived suppressor cells suppressor activity (or reduce negative impact on NK cell activity)
The present application is directed to methods and compositions that are useful for reducing the number of myeloid-derived suppressor cells (MDSC), tumor associated macrophages (TAM), or both in a subject. The methods include administering an antigen binding protein that binds to an antigen expressed by MDSC and/or TAM, or administering a modified T cell or NK-92 cell that expresses an antigen binding protein that binds to an antigen expressed by MDSC and/or TAM, or a combination of both, to a subject. For example, the antigen binding protein can bind to CD33 expressed by MDSC and/or TAM. The methods and compositions are useful for treating a disease associated with MDSC and/or TAM infiltration into a tissue or tumor.
1. A composition comprising a genetically modified T cell or Natural Killer (NK) cell, wherein the modified T cell or NK cell expresses a chimeric antigen receptor (CAR) that specifically targets a tumor-associated antigen, wherein the CAR comprises 1) a first amino acid sequence comprising an antigen binding domain and 2) a second amino acid sequence comprising a CD8 hinge domain, a CD28 transmembrane domain, and an FcεRIγ signaling domain, wherein the second amino acid sequence has at least 95% sequence identity to amino acids 268-401 of SEQ ID NO: 16.
2. The composition of claim 1 , wherein the antigen binding domain is an antibody or fragment thereof, a fusion protein comprising heavy and light chain variable regions, or a single chain variable fragment (scFv).
3. The composition of claim 1 , wherein the composition is formulated for administration to a subject in need thereof.
4. The composition of claim 1 , wherein the genetically modified NK cell further comprises CD16.
5. The composition of claim 4 , further comprising an antibody, fragment thereof, or fusion protein comprised thereof, wherein the antibody specifically binds to CD33.
6. The composition of claim 3 , wherein administration of the composition results in a reduction of cells expressing the antigen.
7. The composition of claim 5 , wherein administration of the composition results in a reduction of cells expressing CD33.
8. The composition of claim 1 , further comprising a T cell or an NK cell genetically modified to express a CAR that specifically binds CD33, wherein the CAR comprises an amino acid sequence having at least 95% sequence identity to SEQ ID NO: 16.
9. The composition of claim 3 , wherein about 1×10 8 to about 1×10 11 modified cells per m 2 of body surface area of the subject are formulated for administration to the subject.
10. The composition of claim 1 , wherein the first amino acid sequence is fused to the N-terminus of the second amino acid sequence.
11. The composition of claim 10 , wherein the first amino acid sequence is fused to the N-terminus of the second amino acid sequence via a polypeptide linker.
12. A method for reducing the number of myeloid-derived suppressor cells (MDSC), tumor associated macrophages (TAM), or both, in a subject in need thereof, the method comprising: administering to the subject, intravenously or by injection, 1) a therapeutically effective amount of a genetically modified NK cell comprising a) a chimeric antigen receptor (CAR) that specifically binds CD33, wherein the CAR comprises a first amino acid sequence comprising a CD33 binding domain and a second amino acid sequence comprising a CD8 hinge domain, a CD28 transmembrane domain, and an FcεRIγ signaling domain, wherein the second amino acid sequence has at least 95% sequence identity to amino acids 268-401 of SEQ ID NO: 16, and b) a CD16 receptor; and 2) a therapeutically effective amount of an antibody.
13. The method of claim 12 , wherein about 1×10 8 to about 1×10 11 modified cells per m 2 of body surface area of the subject are administered to the subject.
14. The method of claim 12 , wherein the genetically modified NK cells are administered once per 1, 2, 3, or 4 weeks.
15. The method of claim 12 , wherein the antibody is specific for a tumor-associated antigen.
16. The method of claim 12 , wherein the antibody is specific for CD33.
17. A composition comprising 1) an effective amount of a genetically modified NK cell comprising a) a chimeric antigen receptor (CAR) that specifically binds CD33, wherein the CAR comprises a first amino acid sequence comprising a CD33 binding domain and a second amino acid sequence comprising a CD8 hinge domain, a CD28 transmembrane domain, and an FcεRIγ signaling domain, wherein the second amino acid sequence has at least 95% sequence identity to amino acids 268-401 of SEQ ID NO: 16, and b) a CD16 receptor; and 2) an effective amount of an antibody.
18. The composition of claim 15 , wherein about 1×10 8 to about 1×10 11 modified NK cells per m 2 of body surface area of the subject are formulated for administration to the subject.
19. The composition of claim 15 , wherein the NK cells are genetically engineered to express a cytokine or variant thereof.
20. The composition of claim 17 , wherein the cytokine or variant thereof comprises IL-2, IL-12, IL-15, IL-18 and IL-21.
21. The composition of claim 17 , wherein the antibody is specific for a tumor-associated antigen.
22. The composition of claim 17 , wherein the antibody is specific for CD33.