Adenovirus and immunomodulator combination therapy
Certain embodiments include the enhancement of effectiveness for an adenoviral cancer therapy.
1. A method for treating and/or preventing a glioma in a mammal in need thereof, comprising administering to the mammal an effective amount of a combination comprising (a) a Delta24-RGD nucleic acid backbone, and a heterologous nucleic acid sequence encoding an OX40 agonist inserted in a nonessential region of the adenovirus genome, wherein the inserted heterologous nucleic acid sequence is under the control of a sequence permitting expression of the OX40 agonist and (b) one or more immune checkpoint inhibitors, wherein said one or more immune checkpoint inhibitor inhibits a checkpoint protein selected from the group consisting of PD-L1, programmed cell death protein 1 (PD-1), and PD-L2.
2. The replication competent oncolytic adenovirus of claim 1 , wherein the OX40 agonist is an OX40 ligand polypeptide.
3. The method of claim 1 , wherein the sequence permitting expression of the OX40 agonist is a CMV or RSV promoter.
4. The method of claim 1 , wherein the adenovirus genome further comprises a heterologous nucleic acid sequence encoding a tumor antigen.
5. The method of claim 1 , wherein the replication competent oncolytic adenovirus and the checkpoint inhibitor are administered simultaneously.
6. The method of claim 1 , wherein the replication competent oncolytic adenovirus and the checkpoint inhibitor are administered sequentially and wherein a first administration of oncolytic adenovirus occurs prior to a first administration of checkpoint inhibitor and preferably occurs within 30 days of a first administration of checkpoint inhibitor.
7. The method of claim 1 , wherein the checkpoint inhibitor is an antibody or fusion protein and is administered as one or more doses of 0.01-10 mg/kg, 0.1-10 mg/kg, 1-10 mg/kg, 2-8 mg/kg, 3-7 mg/kg, 4-5 mg/kg or at least 10 mg/kg.
8. The method of claim 1 , wherein the adenovirus is administered intratumorally, intravascularly, intratumorally and intravascularly or in a neuronal or mesenchymal stem cell carrier.
9. The method of claim 1 , wherein the adenovirus is administered once or multiple times at a dose of 10 8 -10 14 plaque forming units (pfu).
10. The method of claim 1 , wherein the mammal is a human.
11. The method of claim 10 , wherein the human has failed one or more treatments with an immune checkpoint inhibitor.
12. A method for treating and/or preventing cancer and/or treating and/or preventing a metastasis in a human subject in need thereof, comprising administering to the subject an effective amount of a replication competent oncolytic adenovirus according to claim 1 , wherein the immune checkpoint inhibitor and optionally the immune cell co-stimulatory receptor agonist is expressed in a cancer cell of the subject.
13. The method according to claim 1 wherein said wherein said one or more immune checkpoint inhibitor inhibits PD-1.
14. The method according to claim 13 , wherein said inhibitor of PD-1 is selected from the group consisting of Nivolumab, Pembrolizumab, and Pidilizumab.