Oncolytic virotherapy and immunotherapy

1. A method of treating a cancer, comprising administering to a subject:

(i) an oncolytic adenovirus comprising a recombinant adenoviral nucleic acid comprising a nucleic sequence encoding an E1A protein that contains a deletion in its retinoblastoma (Rb) protein-binding region;

(ii) a helper-dependent adenovirus comprising a recombinant adenoviral nucleic acid encoding IL-12, an antagonist anti-PD-L1 antibody, and an enzyme that catalyzes conversion of a non-toxic prodrug to an active cytotoxic form; and

(iii) at least one T cell comprising a chimeric antigen receptor (CAR), wherein the CAR comprises an antigen binding domain capable of specific binding to HER2;

wherein the cancer comprises cells expressing HER2.

2. The method according to claim 1 , wherein the oncolytic virus encodes an E1A protein which displays reduced binding to Rb protein as compared to E1A protein encoded by Ad5.

3. The method according to claim 1 , wherein the deletion comprises deletion of the amino acid sequence LTCHEACF (SEQ ID NO:52).

4. The method according to claim 1 , wherein the oncolytic virus encodes an E1A protein comprising, or consisting of, the amino acid sequence SEQ ID NO:34.

5. The method according to claim 1 , wherein the CAR comprises an antigen-binding domain comprising:

a VL domain comprising:

LC-CRD1: SEQ ID NO:10;

LC-CRD2: SEQ ID NO:11;

LC-CRD3: SEQ ID NO:12;

and a VH domain comprising:

HC-CRD1: SEQ ID NO:13;

HC-CRD2: SEQ ID NO:14;

HC-CRD3: SEQ ID NO:15;

or

a VL domain comprising:

LC-CRD1: SEQ ID NO:18;

LC-CRD2: SEQ ID NO:19;

LC-CRD3: SEQ ID NO:20;

and a VH domain comprising:

HC-CRD1: SEQ ID NO:21;

HC-CRD2: SEQ ID NO:22;

HC-CRD3: SEQ ID NO:23;

or

a VL domain comprising:

LC-CRD1: SEQ ID NO:26;

LC-CRD2: SEQ ID NO:27;

LC-CRD3: SEQ ID NO:28;

and a VH domain comprising:

HC-CRD1: SEQ ID NO:29;

HC-CRD2: SEQ ID NO:30;

HC-CRD3: SEQ ID NO:31;

or

a VL domain comprising:

LC-CRD1: SEQ ID NO:57;

LC-CRD2: SEQ ID NO:58;

LC-CRD3: SEQ ID NO:59;

and a VH domain comprising:

HC-CRD1: SEQ ID NO:60;

HC-CRD2: SEQ ID NO:61;

HC-CRD3: SEQ ID NO:62.

6. The method according to claim 1 , wherein the CAR comprises an antigen binding domain comprising:

a VL comprising, or consisting of, an amino acid sequence having at least 90% sequence identity to SEQ ID NO:16 and a VH comprising, or consisting of, an amino acid sequence having at least 90% sequence identity to SEQ ID NO:17;

or

a VL comprising, or consisting of, an amino acid sequence having at least 90% sequence identity to SEQ ID NO:24 and a VH comprising, or consisting of, an amino acid sequence having at least 90% sequence identity to SEQ ID NO:25;

or

a VL comprising, or consisting of, an amino acid sequence having at least 90% sequence identity to SEQ ID NO:32 and a VH comprising, or consisting of, an amino acid sequence having at least 90% sequence identity to SEQ ID NO:33;

or

a VL comprising, or consisting of, an amino acid sequence having at least 90% sequence identity to SEQ ID NO:63 and a VH comprising, or consisting of, an amino acid sequence having at least 90% sequence identity to SEQ ID NO:64.

7. The method according to claim 1 , wherein the enzyme is selected from: thymidine kinase, cytosine deaminase, nitroreductase, cytochrome P450, carboxypeptidase G2, purine nucleoside phosphorylase, horseradish peroxidase and carboxylesterase.

8. The method according to claim 1 , wherein the enzyme is HSV-1 thymidine kinase.

9. The method according to claim 1 , wherein the method of treating a cancer comprises:

(a) isolating at least one cell from a subject;

(b) modifying the at least one cell to express or comprise a CAR specific for a cancer cell antigen, or a nucleic acid encoding a CAR specific for a cancer cell antigen,

(c) optionally expanding the modified at least one cell, and;

(d) administering the modified at least one cell to a subject.

10. The method according to claim 1 , wherein the cancer is selected from head and neck cancer, nasopharyngeal carcinoma (NPC), cervical carcinoma (CC), oropharyngeal carcinoma (OPC), gastric carcinoma (GC), hepatocellular carcinoma (HCC) and lung cancer.