Treatment of cancer with larazotide derivatives in combination with immune checkpoint inhibitors
The present invention provides compositions and methods for treating a patient having cancer, as well as methods for potentiating an immune checkpoint inhibitor therapy. The methods comprise administering larazotide or a derivative thereof such as (d)-larazotide to a subject in need, including subjects undergoing checkpoint inhibitor therapy, and subjects scheduled to undergo immune checkpoint inhibitor therapy.
1. A method for treating cancer in a patient undergoing an immune checkpoint inhibitor therapy targeting immune checkpoints selected from PD-1, PD-L1, and CTLA-4, the method comprising administering to the gastrointestinal tract of said patient an oral dosage composition comprising an amount effective to potentiate the immune checkpoint inhibitor therapy against the cancer of a peptide having the amino acid sequence of SEQ ID NO: 1, or a pharmaceutically acceptable salt thereof, with the proviso that all non-glycine amino acid residues of SEQ ID NO: 1 are in (d) form.
2. The method of claim 1 , wherein the immune checkpoint inhibitor is selected from ipilimumab, tremelimumab, pembrolizumab and nivolumab.
3. The method of claim 1 , wherein the patient showed no response or only partial response to prior treatment with an immune checkpoint inhibitor therapy.
4. The method of claim 3 , wherein the prior immune checkpoint inhibitor therapy was a PD-1 blockade therapy.
5. The method of claim 1 , wherein the peptide is administered in a pharmaceutical composition that does not substantially release peptide in the stomach, and releases the peptide in the small intestine and/or large intestine.
6. The method of claim 5 , wherein the peptide is released in one or more of the duodenum, jejunum, and the ileum.
7. The method of claim 5 , wherein the peptide is released in the large intestine.
8. The method of claim 7 , wherein the peptide is released in the colon.
9. The method of claim 5 , wherein the peptide is administered in a sustained release formulation that releases peptide in the gastrointestinal tract for at least 2 hours.
10. The method of claim 9 , wherein the sustained release formulation releases peptide in the gastrointestinal tract for at least 3 hours.
11. The method of claim 1 , wherein the peptide is administered from 1 to 3 times per day.
12. The method of claim 11 , wherein the peptide is administered throughout the immune checkpoint inhibitor therapy.
13. The method of claim 12 , wherein the peptide is further administered after the immune checkpoint inhibitor therapy.
14. The method of claim 11 , wherein the peptide is additionally administered for at least one week prior to initiation of the immune checkpoint inhibitor therapy.
15. The method of claim 14 , wherein the peptide is administered throughout the duration of the immune checkpoint inhibitor therapy.
16. The method of claim 15 , wherein the peptide is further administered after the checkpoint inhibitor therapy.
17. The method if claim 1 , wherein the patient has primary cancer.
18. The method of claim 1 , wherein the patient has metastatic cancer.
19. The method of claim 18 , wherein the patient has metastatic melanoma.
20. The method of claim 1 , wherein the patient has colorectal cancer.
21. The method of claim 1 , wherein the patient has sarcoma or carcinoma.
22. The method of claim 1 , wherein the patient has a hematological cancer.
23. The method of claim 22 , wherein the patient has a leukemia, myeloma, or lymphoma.