Combination therapy for use in cancer therapy

Patent metadata

Field	Value
Publication number	US-2016228530-A1
Application number	US-201514882749-A
Country	US
Kind code	A1
Filing date	Oct 14, 2015
Priority date	Oct 14, 2014
Publication date	Aug 11, 2016
Grant date	—

Abstract

The present invention provides methods of treating anal or vaginal tumors and cancers, comprising the step of administering to a subject a combination therapy comprising a chemo-radiation therapy and a recombinant Listeria strain.

First claim

1 . A method of treating an anal or vaginal tumor anal or vaginal cancer, or an anal or vaginal neoplasia in a human subject, the method comprising the step of administering to said subject a combination therapy comprising a chemo-radiation therapy and a recombinant Listeria strain, said Listeria strain comprising a recombinant nucleic acid, said nucleic acid comprising a first open reading frame encoding a recombinant polypeptide comprising an N-terminal fragment of an LLO protein fused to a heterologous antigen or fragment thereof, thereby treating said anal or vaginal tumor anal or vaginal cancer, or an anal or vaginal neoplasia in said human subject.

2 . The method of claim 1 , wherein said tumor, cancer, or neoplasia is an intraepithelial cancer or neoplasia.

3 . (canceled)

4 . The method of claim 1 , wherein said chemo-radiation therapy is administered following a first administration of said recombinant Listeria strain.

5 . The method of claim 1 , wherein said chemo-radiation therapy is administered prior to the administration of said recombinant Listeria strain.

6 . The method of claim 1 , wherein said chemo-radiation therapy is administered following a first administration of said recombinant Listeria strain and prior to one to three booster administrations of said recombinant Listeria strain.

7 . The method of claim 1 , wherein said chemo-radiation therapy is administered concurrently with said recombinant Listeria strain.

8 . The method of claim 1 , wherein said method comprises administering four doses of said recombinant Listeria.

9 . The method of claim 8 , wherein the first dose of said recombinant Listeria is administered prior to chemo-radiation therapy and the 2 nd -4 th doses are administered every 28 days after completion of radiation.

10 . The method of claim 8 , wherein the first dose of said recombinant Listeria is administered before chemo-radiation therapy, wherein the second dose of said recombinant Listeria is administered during chemo-radiation therapy, and wherein the 3 rd -4 th doses are administered every 28 days following the completion of chemo-radiation therapy.

11 . The method of claim 1 , wherein said chemo-radiation therapy comprises mitomycin and fluorouracil (5-FU) and radiation therapy.

12 . The method of claim 11 , wherein said chemo-radiation therapy comprises administering 2 courses of mitomycin, 5-FU with concurrent radiation (54 Gy in 30 fractions by intensity modulated radiation therapy).

13 . The method of claim 11 , wherein said radiation therapy lasts about 6 weeks.

14 . The method of claim 1 , wherein said Listeria comprises a mutation or deletion in the endogenous prfA gene.

15 . The method of claim 14 , wherein said recombinant nucleic acid further comprises a second open reading frame encoding a mutant prfA gene, wherein said mutant prfA gene complements the prfA genomic mutation or deletion, thereby inducing an immune response against said anal or vaginal tumor or anal or vaginal cancer.

16 . The method of claim 15 , wherein said mutant prfA gene encodes a PrfA protein comprising a D133V mutation.

17 . (canceled)

18 . The method of claim 1 , wherein said administering is intravenous or oral administering.

19 . The method of claim 1 , wherein said N-terminal fragment of an LLO protein comprises SEQ ID NO: 2.

20 . The method of claim 1 , wherein said recombinant Listeria strain is administered to said human subject at a dose of 1×10 9 -3.31×10 10 organisms.

21 . The method of claim 1 , wherein said recombinant Listeria strain is a recombinant Listeria monocytogenes strain.

22 . The method of claim 1 , wherein said recombinant Listeria strain has been passaged through an animal host, prior to the step of administering.

23 . The method of claim 1 , wherein said recombinant polypeptide is expressed by said recombinant Listeria strain.

24 . The method of claim 1 , wherein said recombinant Listeria strain comprises a plasmid that encodes said recombinant polypeptide.

25 . (canceled)

26 . The method of claim 1 , further comprising the step of inoculating said human subject with an immunogenic composition that comprises or directs expression of an HPV16 or HPV18 E6 or E7 antigen.

27 . The method of claim 1 , wherein said recombinant Listeria strain has been stored in a frozen or lyophilized cell bank.

28 . A method for inducing an anti-tumor cytotoxic T cell response in a human subject, comprising the step of administering to said subject the combination therapy of claim 1 .

29 . A method of treating a human subject against a tumor or cancer, comprising the step of administering to said subject the recombinant Listeria strain of claim 1 .

30 . The method of claim 29 , wherein said administering is intravenous or oral administering.

31 . The method of claim 28 , wherein said immune response comprises increasing a level of interferon-gamma producing cells, increasing a level of TNF-alpha producing cells, or both.

32 . (canceled)

33 . The method of claim 28 , wherein said immune response comprises an increase of tumor infiltration by T effector cells.

34 . The method of claim 33 , wherein said T effector cells are CD8+T cells or CD4+T cells.

35 . The method of claim 28 , wherein said immune response further comprises epitope spreading, induction of broad-based response to self-derived tumor antigens, or both.

36 . (canceled)

37 . The method of claim 28 , wherein said immune response further comprises improvement of the overall balance of suppressor and effector immune cells in the tumor microenvironment or improvement in the systemic balance of suppressor and effector immunocytes.

38 - 150 . (canceled)

151 . The method claim 12 , wherein said radiation therapy lasts about 6 weeks.

152 . The method of claim 1 , wherein said heterologous antigen is an HPV16 or HPV18 E6 or E7 antigen.

Assignees

• Univ Pennsylvania

Inventors

• Paterson Yvonne

Classifications

• A61K39/12 Primary

  Viral antigens · CPC title

• A61K2039/523

  expressing foreign proteins · CPC title

• A61K2039/6037

  Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT] · CPC title

• A61K2039/522

  avirulent or attenuated · CPC title

• A61K31/513

  having oxo groups directly attached to the heterocyclic ring, e.g. cytosine · CPC title