Combined chemo-immunotherapy with liposomal drugs and cytokines

• US 6,787,132 B1
• Filed: 08/03/2000
• Issued: 09/07/2004
• Est. Priority Date: 12/04/1997
• Status: Expired due to Fees

• Current Assignee: Hadasit Medical Research Services & Development Ltd (Hadassah, The Women's Zionist Organization of America, Inc.), Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Original Assignee: Hadasit Medical Research Services & Development Ltd (Hadassah, The Women's Zionist Organization of America, Inc.), Yissum Research Development Company of the Hebrew University of Jerusalem Ltd. (Hebrew University of Jerusalem)
• Inventors: Barenholz, Yechezkel, Kedar, Eliezer, Gabizon, Alberto A.
• Primary Examiner(s): Weber, Jon P.
• Application Number:
  US09/555,674
• Time in Patent Office: 1,496 Days
• Field of Search: 424/85.1, 424/85.2, 424/85.4, 424/85.5, 424/85.6, 424/85.7, 530/351, 544/100
• US Class Current: 424/85.2
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 38/21 Interferons [IFN]
• CPC Class Codes: A61K 9/1271 Non-conventional liposomes, e.g. PEGylated liposomes, liposomes coated with polymers liposome as conjugate A61K47/6911

Abstract

A method of antitumor therapy is described in which administration of a chemotherapeutic drug, encapsulated in liposomes, is supplemented by administration of an immunostimulating cytokine. The cytokine is preferably also encapsulated in liposomes. In tumor models for lung and colon carcinomas, this method produced a significantly greater therapeutic effect, as evidenced by survival rate and tumor size, than a combination of the effects produced by the free or liposome-encapsulated components administered individually.

Claims

1. A method for antitumor therapy, comprising

administering to a subject in need of such treatment, a therapeutically effective amount of a non-encapsulated chemotherapy drug and an immunostimulating cytokine,

wherein the cytokine is encapsulated in multilamellar liposomes (MLV),

said treatment being characterized in that the subject is administered on non-consecutive days with two or more DOSES of said liposome encapsulated cytokine,

a first dose being administered at least 3 days following administration of said chemotherapeutic drug,

wherein the time between administrations is such that the therapeutic effect of the combined administrations is greater than the sum of the therapeutic effects produced by administration of said chemotherapeutic drug alone and by administration of said immunostimulating cytokine alone.

2. The method of claim 1, wherein said cytokine is selected from the group consisting of interleukin-2 (IL-2), IL-12, IL-15, IL-18, INF-γ

, INF-α

, INF-β

, G-CSF, and GM-CSF.

3. The method of claim 2, wherein said cytokine is IL-2.

4. The method of claim 1, wherein the liposomes comprise at least one lipid selected from the group consisting of dimyristoyl phosphatidyl choline (DMPC), dimyristoyl phosphatidyl glycerol (DMPG), 1,2-distearoyl-3-trimethylammonium propane (DSTAP), phosphatidyl choline, phosphatidyl ethanolamine and cholesterol.

5. The method of claim 4, wherein said cytokine is encapsulated in liposomes comprising (1) DMPC and (2) at least one additional lipid selected from the group consisting of dimyristoyl phosphatidyl glycerol (DMPG), and 1,2-distearoyl-3-trimethylammonium propane (DSTAP), said at least one additional lipid being in an amount of up to 50%.

6. The method of claim 5, wherein said liposome is composed of DMPC and DMPG.

7. The method of claim 6, wherein the liposome comprise DMPC and DMPG in a molar ratio of about 9:

1.

8. The method of claim 1, wherein said chemotherapeutic drug is selected from the group consisting of a chemotherapeutic anthraquinone, cisplatin, and a topoisomerase I inhibitor.

9. The method of claim 8, wherein said chemotherapeutic drug is doxorubicin (adriamycin).

10. A method for antitumor therapy, comprising

administering to a subject in need of such treatment, a therapeutically effective amount of a chemotherapeutic drug encapsulated in liposomes and an immunostimulating cytokine encapsulated in MLV,

said treatment being characterized in that the subject is administered on non-consecutive days with two or more doses of said MLV encapsulated cytokine,

a first dose of said MLV encapsulated cytokine being administered at least 3 days following administration of said liposome encapsulated chemotherapeutic drug,

wherein the time between administration of said MLV encapsulated chemotherapeutic drug and said liposome encapsulated cytokine is such that the combined therapeutic effect of said administrations is greater than a sum of the therapeutic effect produced by administration of the liposome encapsulated chemotherapeutic drug alone by administration of said MLV encapsulated immunostimulating cytokine alone.

11. The method of claim 10, wherein said cytokine is selected from the group consisting of interleukin-2 (IL-2), IL-12, IL-15, IL-18, INF-γ

, INF-α

, INF-β

, G-CSF, and GM-CSF.

12. The method of claim 11, wherein said cytokine is IL-2.

13. The method of claim 10, wherein the MLV encapsulating said immunostimulating cytokine comprise at least one lipid selected from the group consisting DMPC, DMPG, DSTAP, phosphatidyl choline, phosphatidyl ethanolamine and cholesterol.

14. The method of claim 13, wherein said cytokine is encapsulated in MLV comprising (1) DMPC and (2) at least one additional lipid selected from the group consisting of DMPG and DSTAP, said at least one additional lipid being in an amount of up to 50%.

15. The method of claim 14, wherein said MLV comprise of DMPC and DMPG.

16. The method of claim 15, wherein the MLV DMPC and DMPG are present in a molar ratio of about 9:

1.

17. The method of claim 10, wherein the liposomes encapsulating said chemotherapeutic drug comprise 1-10 mole percent of a lipid having a polar head group dericatized with a polyethylene glycol chain which has a molecular weight of between 750 and 10,000 dalton.

18. The method of claim 10, wherein said chemotherapeutic drug is selected from the group consisting of a chemotherapeutic anthraquinone, cisplatin, and a topoisomerase I inhibitor.

19. The method of claim 18, wherein said chemotherapeutic drug is doxorubicin (adriamycin).

20. The method of claim 19, wherein said chemotherapeutic drug is polyethylene glycol-coated liposomal doxorubicin.