Xenogeneic antigen presenting cells and uses thereof

Abstract

The present disclosure relates to methods for treating a tumor in a subject via administering (e.g, by intratumoral injection) a composition comprising antigen presenting cells obtained from a species that is different than the subject, i.e., xenogeneic antigen presenting cells. The source of such xenogeneic antigen presenting cells could be one or more swine. The present disclosure also relates to methods of treating tumors via administering the xenogeneic antigen presenting cells in combination with other anti-cancer therapies. Furthermore, the present disclosure relates to pharmaceutical compositions comprising xenogeneic antigen presenting cells.

Description

This disclosure relates to a method for treating a tumor of a subject by administering (e.g., via intratumoral injection) a composition comprising antigen-presenting cells (i.e., xenogeneic antigen-presenting cells) derived from a species different from that of the subject. The source of such xenogeneic antigen-presenting cells may be one or more pigs. This disclosure also relates to a method for treating a tumor by administering the xenogeneic antigen-presenting cells in combination with other anticancer therapies. Furthermore, this disclosure relates to pharmaceutical compositions comprising xenogeneic antigen-presenting cells. Abstract

Claims

WHAT IS CLAIMED IS:

1. A method for treating a tumor in a subject in need thereof, the method comprising: administering a composition comprising antigen presenting cells to the subject, wherein the antigen presenting cells are obtained from a species that is different than the subject.

2. The method of claim 1, wherein the tumor is a solid tumor, and the administering is into the tumor of the subject via an intratumoral injection.

3. The method of any one of the preceding claims, wherein the antigen presenting cells are obtained from a species that is a swine.

4. The method of any one of the preceding claims, wherein the antigen presenting cells are obtained from a species that is a miniature swine.

5. The method of any one of the preceding claims, wherein the subject is a human.

6. The method of claim 3, wherein the swine is an alpha-1,3 galactosyltransferase- deficient swine.

7. The method of claim 6, wherein the alpha- 1,3 galactosyltransferase-deficient swine is a swine leukocyte antigen (SLA)-inbred swine.

8. The method of claim 4, wherein the miniature swine is an alpha-1,3 galactosyltransferase-deficient miniature swine.

9. The method of claim 8, wherein the alpha-1,3 galactosyltransferase-deficient miniature swine is a swine leukocyte antigen (SLA)-inbred swine.

10. The method of any one of the preceding claims, wherein the method triggers an immune response specific to the tumor.11 . The method of any one of the preceding claims, wherein the method yields an abscopal effect.

12. The method of any one of the preceding claims, wherein the tumor is a solid cancerous tumor.

13. The method of claim 12, wherein the tumor is selected from the group consisting of sarcomas, carcinomas, lymphomas, breast tumors, prostate tumors, head and neck tumors, glioblastomas, bladder tumors, pancreatic tumors, liver tumors, ovarian tumors, colorectal tumors, pulmonary tumors, cutaneous tumors, lymphoid tumors, gastrointestinal tumors, gastrointestinal stromal tumors, cervical tumors, hepatocellular carcinomas, renal cell carcinomas, melanomas, colorectal carcinomas, esophageal carcinomas, brain tumors, kidney tumors, lung tumors (including non-small cell lung cancer), gastric tumors, bile-duct tumors, uterine tumors, and childhood (pediatric) tumors.

14. The method of any one of the preceding claims, wherein the tumor is resistant to treatment to chemotherapy and / or treatment with an immunotherapy.

15. The method of any one of the preceding claims, wherein the antigen presenting cells are derived from one or more swine or miniature swine using a leukapheresis procedure, wherein the leukapheresis procedure generates a leukopak containing peripheral blood mononuclear cells, and the leukopak is further fractionated by counterflow elutriation.

16. The method of any one of the preceding claims, wherein the composition comprising antigen presenting cells is substantially free of pathogens.

17. The method of any one of the preceding claims, wherein the antigen presenting cells are obtained from swine or miniature swine of different genotypes.

18. The method of any one of the preceding claims, wherein the composition comprising antigen presenting cells is administered in single or multiple doses.

19. The method of any one of the preceding claims, wherein the composition comprising antigen presenting cells is administered via an intratumoral injection of at least about 1 x 106antigen presenting cells per dose.

20. The method of any one of the preceding claims, wherein the composition comprising antigen presenting cells is administered via an intratumoral injection of about 1 x106, about 5 x 106, about 10 x 106, about 15 x 106, about 20 x 106, about 25 x 106, about 30 x 106, about 35 x 106, about 40 x 106, about 45 x 106, about 50 x 106, about 55 x 106, about 60 x 106, about 65 x 106, about 70 x 106, about 75 x 106, about 80 x 106, about 85 x 106, about 90 x 106, about 95 x 106, about 10 x 107, about 15 x 107, about 20 x 107, about 25 x 107, about 30 x 107, about 35 x IO7, about 40 x 107, about 45 x IO7, or about 50 x 107antigen presenting cells per dose.

21. The method of any one of the preceding claims, wherein the antigen presenting cells are substantially mature antigen presenting cells.

22. The method of any one of the preceding claims, wherein the antigen presenting cells are not activated or stimulated.

23. The method of any one of the preceding claims, wherein the composition comprises peripheral blood mononuclear cells (PBMC).

24. The method of any one of the preceding claims, wherein the composition comprises monocytes.

25. The method of any one of the preceding claims, wherein the composition comprises dendritic cells, macrophages, granulocytes, T-cells, B-cells, and / or NK cells.

26. The method of any one of the preceding claims, wherein the composition comprises at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or greater than about 95% PBMCs, wherein the PBMCs are mature, immature, or a combination of mature and immature PBMCs.

27. The method of any one of the preceding claims, wherein the composition comprises at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or greater than about 95% monocytes, wherein the monocytes are mature, immature, or a combination of mature and immature monocytes.

28. The method of claim 27, wherein the composition comprises a mixture of at least about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or greater than about 95% monocytes and dendritic cells, wherein the monocytes and / or dendritic cells in said mixture may be mature, immature, or a combination of mature and immature monocytes and / or dendritic cells.

29. The method of claim 28, wherein the mixture comprises from 10% to 95%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 20% to 95%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to40%, 20% to 30%, 30% to 95%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to50%, 30% to 40%, 40% to 95%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to50%, 50% to 95%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 95%, 60% to90%, 60% to 80%, 60% to 70%, 70% to 95%, 70% to 90%, 70% to 80%, 80% to 95%, 80% to90%, 90% to 95%, or greater than 95% monocytes.

30. The method of claim 28, wherein the mixture comprises from 10% to 30%, 35% to 55%, 60% to 80%, or 85% to 95% monocytes.

31. The method of claim 28, wherein the mixture comprises at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or greater than about 95% monocytes.

32. The method of claim 28, wherein the mixture comprises from 10% to 95%, 10% to 90%, 10% to 80%, 10% to 70%, 10% to 60%, 10% to 50%, 10% to 40%, 10% to 30%, 10% to 20%, 20% to 95%, 20% to 90%, 20% to 80%, 20% to 70%, 20% to 60%, 20% to 50%, 20% to 40%, 20% to 30%, 30% to 95%, 30% to 90%, 30% to 80%, 30% to 70%, 30% to 60%, 30% to50%, 30% to 40%, 40% to 95%, 40% to 90%, 40% to 80%, 40% to 70%, 40% to 60%, 40% to50%, 50% to 95%, 50% to 90%, 50% to 80%, 50% to 70%, 50% to 60%, 60% to 95%, 60% to90%, 60% to 80%, 60% to 70%, 70% to 95%, 70% to 90%, 70% to 80%, 80% to 95%, 80% to90%, 90% to 95%, or greater than 95% dendritic cells.

33. The method of claim 28, wherein the mixture comprises from 10% to 30%, 35% to 55%, 60% to 80%, or 85% to 95% dendritic cells.

34. The method of claim 28, wherein the mixture comprises at least about 10%, about 15%, about 20%, about 25%, about 30%, about 35%, about 40%, about 45% about 50%, about 55%, about 60%, about 65%, about 70%, about 75%, about 80%, about 85%, about 90%, about 95%, or greater than about 95% dendritic cells.

35. The method of any one of the preceding claims, wherein the subject is receiving another anti-cancer therapy.

36. The method of claim 35, wherein the other anti-cancer therapy comprises treatment with one or more immune checkpoint inhibitors.

37. The method of claim 35, wherein the other anti-cancer therapy is an anti-CTLA4 therapy, anti-PDl therapy, anti-PDLl therapy, anti-LAG-3 therapy, tumor-treating fields (TTFs), cell-based therapy, a tyrosine kinase inhibitor, a VEGF inhibitor, or any combination thereof.

38. The method of claim 35, wherein the other anti-cancer therapy comprises treatment with imatinib, sunitinib, regorafenib, pazopanib, nilotinib, avapritinib, ripretinib, sorafenib, pimitespib, ipilimumab, tremelimumab, nivolumab, pembrolizumab, cemiplimab, atelizumab, avelumab, durvalumab, relatlimab, or any combination thereof.

39. The method of any one of claims 35 to 38, wherein the subject does not respond to the other anti-cancer therapy in the absence of administration of the composition comprising antigen presenting cells.

40. A pharmaceutical composition suitable for intratumoral injection, wherein the pharmaceutical composition comprises antigen presenting cells obtained from one or more swine.

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