Combination therapy of immunotoxin and checkpoint inhibitor
Regional, tumor-targeted, cytotoxic therapy, such as D2C7-immunotoxin (D2C7-IT), not only specifically target and destroy tumor cells, but in the process initiate immune events that promote an in situ vaccine effect. The antitumor effects are amplified by immune checkpoint blockade which engenders a long-term systemic immune response that effectively eliminates all tumor cells.
1. A method of treating a glioma tumor in a patient, comprising:
administering to the patient an immunotoxin comprising a single chain variable region antibody fused to a PE38 truncated Pseudomonas exotoxin, wherein the single chain variable region antibody has CDR1, CDR2, and CDR3 regions as shown in SEQ ID NO: 6-11; and
administering an inhibitor of an immune checkpoint to the patient, wherein the immune checkpoint is selected from the group consisting of PD-1 and CTLA-4.
2. The method of claim 1 wherein the tumor is a malignant glioma.
3. The method of claim 1 wherein the immunotoxin is administered directly to the tumor.
4. The method of claim 1 wherein the checkpoint inhibitor is an anti-PD-1 antibody.
5. The method of claim 1 wherein the checkpoint inhibitor is an anti-CTLA4 antibody.
6. The method of claim 1 wherein the immune checkpoint inhibitor is administered within 30 days of administering the immunotoxin.
7. The method of claim 1 wherein the immune checkpoint inhibitor is administered within 7 days of administering the immunotoxin.
8. The method of claim 1 wherein the PE38 truncated Pseudomonas exotoxin is fused to a KDEL peptide.
9. A kit for treating a glioma tumor, comprising:
an immunotoxin comprising a single chain variable region antibody fused to a PE38 truncated Pseudomonas exotoxin, wherein the single chain variable region antibody has CDR1, CDR2, and CDR3 regions as shown in SEQ ID NO: 6-11; and
an inhibitor of an immune checkpoint, wherein the immune checkpoint is selected from the group consisting of PD-1 and CTLA-4.
10. The kit of claim 9 wherein the checkpoint inhibitor is an anti-PD-1 antibody.
11. The kit of claim 9 wherein the checkpoint inhibitor is an anti-CTLA4 antibody.
12. The kit of claim 9 wherein the PE38 truncated Pseudomonas exotoxin is fused to a KDEL peptide.
13. The method of claim 1 wherein the immunotoxin comprises the amino acid sequence of SEQ ID NO: 1.
14. The method of claim 1 wherein the immunotoxin comprises the amino acid sequence of SEQ ID NO: 2.
15. The method of claim 1 wherein the immunotoxin comprises the amino acid sequence of SEQ ID NO: 3.
16. The method of claim 1 wherein the immunotoxin comprises the amino acid sequence of SEQ ID NO: 4.
17. The method of claim 1 wherein the immunotoxin comprises the amino acid sequence of SEQ ID NO: 5.
18. The kit of claim 9 wherein the immunotoxin comprises the amino acid sequence of SEQ ID NO: 1.
19. The kit of claim 9 wherein the immunotoxin comprises the amino acid sequence of SEQ ID NO: 2.
20. The kit of claim 9 wherein the immunotoxin comprises the amino acid sequence of SEQ ID NO: 3.
21. The kit of claim 9 wherein the immunotoxin comprises the amino acid sequence of SEQ ID NO: 4.
22. The kit of claim 9 wherein the immunotoxin comprises the amino acid sequence of SEQ ID NO: 5.