T-cell vaccination with viral vectors via mechanical epidermal disruption

• US 9,416,371 B2
• Filed: 01/27/2014
• Issued: 08/16/2016
• Est. Priority Date: 10/31/2008
• Status: Active Grant

• Current Assignee: Tremrx Incorporated
• Original Assignee: Tremrx Incorporated
• Inventors: Kupper, Thomas S., Liu, Luzheng Lisa, Clark, Rachel A.
• Primary Examiner(s): CHEN, STACY BROWN
• Application Number:
  US14/165,126
• Publication Number:
  US 20140186298A1
• Time in Patent Office: 932 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/5254 avirulent or attenuated
• CPC Class Codes: A61K 2039/5256 expressing foreign proteins
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 38/177 Receptors; Cell surface antigens; Cell surface determinants
• CPC Class Codes: A61K 38/18 Growth factors; Growth regulators
• CPC Class Codes: A61K 38/1825 Fibroblast growth factor [FGF]
• CPC Class Codes: A61K 38/19 Cytokines; Lymphokines; Interferons
• CPC Class Codes: A61K 38/193 Colony stimulating factors [CSF]
• CPC Class Codes: A61K 38/20 Interleukins [IL]
• CPC Class Codes: A61K 38/2006 IL-1
• CPC Class Codes: A61K 38/2013 IL-2
• CPC Class Codes: A61K 38/2046 IL-7
• CPC Class Codes: A61K 38/208 IL-12
• CPC Class Codes: A61K 38/2086 IL-13 to IL-16
• CPC Class Codes: A61K 39/12 Viral antigens
• CPC Class Codes: A61K 39/285 Vaccinia virus or variola virus
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 31/06 for tuberculosis
• CPC Class Codes: A61P 31/10 Antimycotics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 : for RNA viruses
• CPC Class Codes: A61P 31/16 : for influenza or rhinoviruses
• CPC Class Codes: A61P 31/18 : for HIV
• CPC Class Codes: A61P 33/02 : Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis
• CPC Class Codes: A61P 33/06 : Antimalarials
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: C12N 15/86 : Viral vectors
• CPC Class Codes: C12N 2710/24134 : Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
• CPC Class Codes: C12N 2710/24143 : viral genome or elements thereof as genetic vector
• CPC Class Codes: Y02A 50/30 : Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

Attenuated, replication-deficient viruses such as vaccinia viruses are used to deliver an exogenous viral, bacterial, parastic or tumor antigen to an epidermal tissue such as the skin, lungs or gastrointestinal tract, which has been mechanically disrupted, in an amount effective to elicit or stimulate a cell mediated immune response. The epidermis may be mechanically disrupted prior to, at the same time, or immediately after the administration of the vaccine. The vaccine can be used to induce immunity against a pathogen, such as a virus, bacteria, or parasite, or against a cancer in a subject that has or is at risk of developing cancer.

Claims

1. A method for inducing or stimulating a T cell mediated immune response to an exogenous T cell antigen in epithelial tissues of a human subject comprising

administering to the epithelial tissue of the subject a live, modified, non-replicating poxvirus expressing the antigen to cause a local infection in the epithelial skin tissue in an amount sufficient to cause the infected cells to express viral proteins, the exogenous T cell antigen and inflammatory factors and stimulate a T cell immune response in the lymph nodes to the exogenous T cell antigen,

wherein the live, modified, poxvirus expressing the antigen is administered to epithelial skin tissue that is disrupted to penetrate the stratum corneum without penetrating the entire epidermis.

2. The method of claim 1, wherein the virus is selected from the group consisting of:

orthopox, suipox, avipox, capripox, leporipox, parapoxvirus, molluscpoxvirus, and yatapoxvirus.

3. The method of claim 2, wherein the orthopox virus is a vaccinia virus.

4. The method of claim 2, wherein the vaccinia virus is derived by natural or artificial modification of a virus selected from the group consisting of:

WR strain, Wyeth strain, ACAM2000, Lister strain, LC16m8, Elstree-BNm, Copenhagen strain, and Tiantan strain.

5. The method of claim 1, wherein the live, modified, poxvirus expressing the antigen is delivered at the same time as the skin is disrupted to penetrate the stratum corneum without penetrating the entire epidermis.

6. The method of claim 1, wherein the subject has or is at risk of developing cancer and the antigen is a tumor-associated antigen (TAA), a tumor-specific antigen (TSA), or a tissue-specific antigen.

7. The method of claim 6, wherein the cancer is in or derived from the skin, oral mucosa, esophagus, reproductive and urogenital mucosa.

8. The method of claim 6, wherein the cancer is selected from the group consisting of melanoma, squamous cell carcinoma, basal cell carcinoma, Merkel cell carcinoma, adenexal carcinoma, cutaneous T or B cell lymphoma, sarcomas, adenocarcinoma, prostate adenocarcinoma, prostatic intraepithelial neoplasia, squamous cell lung carcinoma, lung adenocarcinoma, small cell lung carcinoma, ovarian cancer of epithelial origin, colorectal adenocarcinoma and leiomyosarcoma, stomach adenocarcinoma and leiomyosarcoma, hepatocellular carcinoma, cholangiocarcinoma, ductal adenocarcinomas of pancreas, endocrine pancreatic tumors, renal cell carcinoma, transitional cell carcinoma of kidney and bladder, and bladder squamous cell carcinoma.

9. The method of claim 1, wherein the subject has or is at risk of developing a viral, bacterial, fungal, or protozoal infection and the antigen is a viral, bacterial, fungal or protozoal antigen.

10. The method of claim 9, wherein the viral infection is selected from the group consisting of:

HIV, influenza, dengue, Hepatitis A virus, Hepatitis B virus, Hepatitis C virus, human papilloma virus, Ebola, Marburg, Rabies, Hanta virus infection, West Nile virus, SARS-like Coronaviruses, Herpes simplex virus, Varicella-zoster virus, Epstein-Barr virus, Human herpesvirus 8, Alpha viruses, and St. Louis encephalitis, the bacterial infection is selected from the group consisting of;

Mycobacterium tuberculosis, Salmonella typhi, Bacillus anthracis, Yersinia perstis, Francisella tularensis, Legionella, Chlamydia, Rickettsia typhi, and Treponema pallidum, the fungal infection is selected from the group consisting of;

Coccidioides immitis, Blastomyces dermatitidis, Cryptococcus neoformans, Candida albicans, and Aspergillus species, and the protozoal infection is selected from the group consisting of;

Plasmodium falciparum, Plasmodium vivax, Plasmodium ovale, Plasmodium malariae, Leishmania species, African Trypanosome species, American Trypanosome species, cryptosporidiums, isospora species, Naegleria fowleri, Acanthamoeba species, Balamuthia mandrillaris, Toxoplasma gondii, and Pneumocystis carinii.

11. The method of claim 1, further comprising administering or co-expressing a co-stimulatory molecule, a growth factor, an adjuvant and/or a cytokine, before, at the same time, or after the antigen, at the same or a distant site.

12. The method of claim 11, wherein the co-expressed co-stimulatory molecule is selected from the group consisting of:

IL-1, IL-2, IL-7, IL-12, IL-15, IL-18, IL-23, IL-27, B7-2, B7-H3, CD40, CD40L, ICOS-ligand, OX-40L, 4-1BBL, GM-CSF, SCF, FGF, Flt3-ligand, CCR4.

13. A kit for inducing or stimulating a T cell-mediated immune response to an exogenous T cell antigen in human epithelial tissues comprising

a device for delivering poxvirus to a human subject'"'"'s epidermal tissue, wherein the device penetrates the stratum corneum without penetrating the entire epidermis, and

a live, modified, non-replicating poxvirus expressing an antigen in an amount sufficient to cause a local infection in the epithelial tissue, and stimulate a T cell immune response in the lymph nodes to the exogenous T cell antigen when administered to epidermal tissue.