Modified vaccinia Ankara expressing p53 in cancer immunotherapy

• US 7,256,037 B2
• Filed: 12/23/2003
• Issued: 08/14/2007
• Est. Priority Date: 12/23/2002
• Status: Active Grant

• Current Assignee: City of Hope
• Original Assignee: City of Hope
• Inventors: Diamond, Don J., Ellenhorn, Joshua D. I.
• Primary Examiner(s): Foley; Shanon
• Assistant Examiner(s): Goddard; Laura B
• Application Number:
  US10/746,558
• Publication Number:
  US 20040208850A1
• Time in Patent Office: 1,330 Days
• Field of Search: 424/93.2
• US Class Current: 435/320.1
• CPC Class Codes: A61K 2039/5156 expressing foreign proteins
• CPC Class Codes: A61K 2039/55516 Proteins; Peptides
• CPC Class Codes: A61K 2039/55561 CpG containing adjuvants; Oligonucleotide containing adjuvants
• CPC Class Codes: A61K 2039/57 characterised by the type of response, e.g. Th1, Th2
• CPC Class Codes: A61P 35/00 Antineoplastic agents
• CPC Class Codes: A61P 37/04 Immunostimulants
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/4746 p53
• CPC Class Codes: C12N 15/86 Viral vectors
• CPC Class Codes: C12N 2710/24143 viral genome or elements thereof as genetic vector
• CPC Class Codes: Y10S 435/81 Packaged device or kit

Abstract

Mutations to the tumor suppressor protein p53 have been observed in 40-60% of all human cancers. These mutations are often associated with high nuclear and cytoplasmic concentrations of p53. Since many tumors exhibit highly elevated p53 levels, the protein is an attractive target for cancer immunotherapy. Unfortunately, p53 is an autoantigen that is likely to be tolerated as a self-protein by the immune system. The present invention is based on the discovery that this self-tolerance can be overcome by administration of recombinant modified vaccinia Ankara (MVA) containing a nucleic acid that encodes p53 (rMVAp53). The invention discloses a method of generating a p53-specific CTL-response to tumor cells expressing mutated p53 by administering a composition comprising rMVAp53. Administration of rMVAp53 decreases tumor development, tumor growth, and mortality in a variety of malignant cell types. These effects are enhanced by administration of CTLA-4 blocker and/or CpG oligodeoxynucleotide immunomodulators.

Claims

1. A composition comprising a recombinant MVA virus (rMVA) containing a nucleic acid sequence encoding wild-type human p53, wherein said nucleic acid sequence comprises the nucleotide sequence of SEQ ID NO:

2.

2. A kit comprising the composition of claim 1 and instructions for administration of said composition to a subject having a p53-expressing malignancy.

3. The kit of claim 2, wherein said subject is human.

4. A composition comprising a recombinant MVA virus (rMVA) containing a nucleic acid sequence encoding wild-type human p53 wherein said wild-type human p53 is encoded by the nucleotide sequence of SEQ ID NO:

2. and wherein said wild-type human p53 is capable of arresting the cell cycle.

5. A kit comprising the composition of claim 4 and instructions for administration of said composition to a subject having a p53-expressing malignancy.