Methods of treating CART-T cell therapy-induced neuroinflammation using a GM-CSF antagonist
Methods for reducing blood-brain barrier disruption in a subject treated with immunotherapy, the method comprising administering a recombinant GM-CSF antagonist to the subject. Methods for preserving blood-brain barrier integrity in a subject treated with immunotherapy, the method comprising administering a recombinant hGM-CSF antagonist to the subject. Methods for decreasing or preventing CAR-T cell therapy-induced neuroinflammation in a subject in need thereof, the method comprising administering a recombinant GM-CSF antagonist to the subject. Methods for preventing or reducing blood-brain barrier disruption in a subject treated with immunotherapy, the method comprising administering CAR-T cells having a GM-CSF gene knockout (GM-CSF k/o CAR-T cells) to the subject.
1. A method for decreasing or preventing CAR-T cell therapy-induced neuroinflammation in a subject in need thereof, the method comprising administering a recombinant hGM-CSF antagonist to the subject, wherein the recombinant hGM-CSF antagonist is anti-hGM-CSF antibody lenzilumab.
2. The method of claim 1 , wherein administering the recombinant hGM-CSF antagonist reduces disruption of the blood-brain-barrier, thereby maintaining integrity thereof.
3. The method of claim 2 , wherein reducing the disruption of the blood-brain-barrier decreases or prevents an influx of pro-inflammatory cytokines into the central nervous system.
4. The method of claim 3 , wherein the pro-inflammatory cytokines are selected from the group consisting of IP-10, IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-1Ra, VEGF, TNF-a, FGF-2, IFN-γ, IL-12p40, IL-12p70, sCD40L, MDC, MCP-1, MIP-1a, MIP-1b, KC, or a combination thereof.
5. The method of claim 1 , wherein neuro-inflammation in the subject is decreased by 75% to 95% compared to a subject treated with CAR-T cell therapy and a control antibody.
6. The method of claim 5 , wherein the 75% to 95% decrease in neuro-inflammation is similar to neuroinflammation in an untreated control subject.
7. The method of claim 1 , wherein the subject is administered chimeric antigen receptor-expressing T-cells (CAR T-cells).
8. The method of claim 7 , wherein the CAR T-cells are CD19 CAR-T cells.
9. The method of claim 1 , wherein the anti-hGM-CSF antibody binds mammalian GM-CSF or binds primate GM-CSF.
10. The method of claim 9 , wherein the primate is a monkey, a baboon, a macaque, a chimpanzee, a gorilla, a lemur, a lorise, a tarsier, a galago, a potto, a sifaka, an indri, an aye-ayes an ape or a human.
11. The method of claim 1 , wherein the anti-hGM-CSF antibody is administered prior to, concurrent with, following CAR-T cell therapy or a combination thereof.
12. The method of claim 1 , wherein the anti-hGM-CSF antibody binds human GM-CSF.
13. The method of claim 1 , wherein the anti-hGM-CSF antibody is a monoclonal antibody.
14. The method of claim 1 , wherein the anti-hGM-CSF antibody is a human GM-CSF neutralizing antibody.
15. The method of claim 1 , wherein the anti-hGM-CSF antibody is a recombinant antibody.
16. The method of claim 1 , wherein the anti-hGM-CSF antibody is an engineered human antibody.
17. The method of claim 1 , wherein the anti-hGM-CSF antibody binds to the same epitope as chimeric 19/2 antibody.
18. The method of claim 1 , wherein the anti-hGM-CSF antibody comprises a VH region that comprises a CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12), a J segment, and a V-segment, wherein the J-segment comprises at least 95% identity to human JH4 (YFDYWGQGTLVTVSS) (SEQ ID NO: 14) and the V-segment comprises at least 90% identity to a human germ line VH1 1-03 sequence.
19. The method of claim 18 , wherein the J segment comprises YFDYWGQGTLVTVSS (SEQ ID NO: 14).
20. The method of claim 18 , wherein the CDR3 comprises RQRFPYYFDY (SEQ ID NO: 15).
21. The method of claim 18 , wherein the anti-hGM-CSF antibody comprises a VH CDR1 and a VH CDR2 as shown in a VH region having a sequence of VH #5 set forth in FIG. 1 .
22. The method of claim 18 , wherein the V-segment sequence has a VH V segment sequence of VH #5 shown in FIG. 1 .
23. The method of claim 18 , wherein the VH has the sequence of VH #5 set forth in FIG. 1 .
24. The method of claim 1 , wherein the anti-hGM-CSF antibody comprises a VL-region that comprises a CDR3 comprising the amino acid sequence FNK.
25. The method of claim 24 , wherein the anti-hGM-CSF antibody comprises a VL region that comprises a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18).
26. The method of claim 24 , where the VL region comprises a CDR1 and CDR2 of a VL region having the sequence of VK #2 shown in FIG. 1 .
27. The method of claim 24 , wherein the VL region comprises a V segment that has at least 95% identity to the VKIII A27 V-segment sequence as shown in FIG. 1 .
28. The method of claim 24 , wherein the VL region has the sequence of VK #2 set forth in FIG. 1 .
29. The method of claim 1 , wherein the anti-hGM-CSF antibody has a VH region CDR3 binding specificity determinant RQRFPY (SEQ ID NO: 12) and a VL region that has a CDR3 comprising QQFNKSPLT (SEQ ID NO: 18).
30. The method of claim 29 , wherein the anti-hGM-CSF antibody has a VH region having sequence VH #5 set forth in FIG. 1 and a VL region having sequence VK #2 set forth in FIG. 1 .
31. The method of claim 29 , wherein the VH region or the VL region, or both the VH and VL region amino acid sequences comprise a methionine at the N-terminus.
32. The method of claim 1 , wherein the subject further has a CAR-T related toxicity selected from cytokine release syndrome, neurotoxicity, or a combination thereof.