Oncolytic virus or antigen presenting cell mediated cancer therapy using type I interferon and CD40-ligand
The invention concerns APCs, such as DCs, comprising a combination of an exogenous type I interferon and an exogenous CD40-L or one or more heterologous nucleic acid sequences encoding a combination of an exogenous type I IFN and an exogenous CD40-L, such as a combination of IFNβ and CD40-L; and methods for treating a malignancy by administering such APCs to a subject in need thereof. In certain embodiments, a subject is treated with an irradiation therapy before administering the APCs, such as DCs, of the invention. The invention also concerns an oncolytic virus comprising a combination of a type I IFN and CD40-L or one or more nucleic acid sequences encoding a combination of a type I IFN and CD40-L, such as a combination of IFNβ and CD40-L; and methods for treating a malignancy by administering such oncolytic virus to a subject in need thereof.
1. An oncolytic virus comprising:
(i) a nucleic acid sequence encoding a type I interferon, wherein the type I interferon is: IFNα comprising at least 80% sequence identity to the human IFNα (SEQ ID NO: 1), IFNβ comprising at least 80% sequence identity to the human IFNβ (SEQ ID NO: 2), IFNε comprising at least 80% sequence identity to the human IFN& (SEQ ID NO: 3), IFNκ comprising at least 80% sequence identity to the human IFNκ (SEQ ID NO: 4), or IFNω comprising at least 80% sequence identity to the human IFN (SEQ ID NO: 5);
(ii) a nucleic acid sequence encoding a CD40-L, which comprises at least 80% sequence identity to a chimeric CD40-L having a sequence selected from SEQ ID NOs: 7 to 18;
(iii) a CMV promoter sequence operatively linked to the nucleic acid sequence encoding the CD40L such that expression of the CD40L is directed by the CMV promoter; and
(iv) an SV40 promoter sequence operatively linked to the nucleic acid sequence encoding the type I interferon such that expression of the type I interferon is directed by the SV40 promoter, wherein the oncolytic virus is recombinant adenovirus.
2. The oncolytic virus of claim 1 , wherein:
the type I interferon is IFNβ comprising at least 80% sequence identity to the human IFNβ (SEQ ID NO: 2) and the CD40-L comprises at least 80% sequence identity to a chimeric CD40-L having a sequence of SEQ ID NO: 12.
3. A composition comprising the oncolytic virus of claim 1 ; and a pharmaceutically acceptable carrier.
4. The composition of claim 3 , further comprising an adjuvant.
5. A method for treating a malignancy, comprising administering to a subject in need thereof an effective amount of the oncolytic virus of claim 1 .
6. The method of claim 5 , wherein the method further comprises administering one or more additional anti-cancer agents to the subject.
7. A method for treating a malignancy, comprising:
(i) administering to a subject in need thereof an effective amount of the oncolytic virus of claim 1 ; and
(ii) conducting hematopoietic cell transplantation on the subject.
8. The oncolytic virus of claim 1 , wherein the nucleic acid sequence encoding a type I interferon was inserted at a deleted adenovirus E3 region and the nucleic acid sequence encoding a CD40-L was inserted upstream of the adenovirus E1A gene region containing a 24 nucleotide deletion.