Combination therapy for treatment of brain cancers

1. A method of treating a subject having brain tumor comprising:

(a) administering an oncolytic adenovirus to said subject;

(b) administering an anti-PD-1 antibody to said subject; and

(c) assessing tumor response by measuring tumor size;

wherein the oncolytic adenovirus is an adenovirus serotype 5 strain, is selectively replication competent in cells defective in the Rb/p16 tumor suppressor pathway, contains a deletion of the 24 nucleotides encoding amino acids 122 to 129 of the adenoviral E1A protein, and/or contains an integrin binding RGD-4C motif; and

wherein the anti-PD-1 antibody is pembrolizumab administered at 200 mg per dose; and

wherein the tumor exhibits reduced growth, no growth, a 10% reduction in tumor mass, a 20% reduction in tumor mass, a 30% reduction in tumor mass, a 40% reduction in tumor mass, a 50% reduction in tumor mass, a 60% reduction in tumor mass, a 70% reduction in tumor mass, an 80% reduction in tumor mass, a 90% reduction in tumor mass, or a 100% reduction in tumor mass following initiation of treatment.

2. The method of claim 1 , wherein the oncolytic adenovirus is DNX-2401.

3. The method of claim 1 , wherein the oncolytic adenovirus is delivered intratumorally.

4. The method of claim 3 , wherein the oncolytic adenovirus is delivered via cannula or needle.

5. The method of claim 1 , wherein the oncolytic adenovirus is delivered at 5×10 8 viral particles per dose, 5×10 9 viral particles per dose, or 5×10 10 viral particles per dose.

6. The method of claim 1 , wherein the anti-PD1 antibody is delivered by intravenous infusion.

7. The method of claim 1 , wherein the anti-PD1 antibody dose is administered over 30 minutes.

8. The method of claim 1 , wherein a single dose of the oncolytic adenovirus is provided prior to three consecutive doses of the anti-PD1 antibody.

9. The method of claim 8 , wherein the time between oncolytic adenovirus administration and the first administration of the anti-PD1 antibody is about 7-9 days.

10. The method of claim 8 , wherein the time between sequential administrations of the anti-PD1 antibody is about three weeks.

11. The method of claim 1 , further comprising administering to the subject one or more of a steroid, an anticonvulsant or an antibody that inhibits vascular endothelial growth factor A.

12. The method of claim 8 , wherein treating further comprises additional administrations of the anti-PD1 antibody for up to 105 weeks or 24 months from the date of oncolytic adenovirus administration.

13. The method of claim 1 , wherein said subject is further evaluated for one of more of overall survival, clinical benefit rate, Karnofsky performance status, neurologic status, cytokine levels, lymphocyte levels, or a biomarker.

14. The method of claim 13 , wherein said biomarker is PD-1 level or PDL-1 level.

15. The method of claim 1 , wherein tumor size is measured by MRI.

16. The method of claim 1 , further comprising stereotactically-guided biopsy of the brain tumor.

17. The method of claim 1 , wherein the brain tumor is glioblastoma multiforme.

18. The method of claim 1 , wherein the brain tumor is gliosarcoma.

19. The method of claim 1 , wherein the subject exhibits an overall survival of at least 9 months, 12 months, 15 months, 18 months, 24 months, 36 months or 48 months, any interval therebetween.

20. The method of claim 1 , wherein the subject exhibits an increase in overall survival, as compared to an untreated control subject, of at least 6 months, 9 months, 12 months, 15 months, 18 months, 24 months, 36 months or 48 months, any interval therebetween.

21. The method of claim 1 , wherein the tumor exhibits reduced growth or no growth following initiation of treatment.

22. The method of claim 1 , wherein the Karnofsky performance status improves or remains unchanged following step (b).

23. The method of claim 1 , wherein there is a statistically measurable clinical benefit.

24. The method of claim 1 , wherein the subject exhibits recurrent or progressive brain tumor following previous treatment.

25. The method of claim 1 , wherein the previous treatment was chemotherapy, radiotherapy, or antibody therapy.

26. The method of claim 1 , wherein the subject is a human.

27. The method of claim 1 , wherein the tumor exhibits a 10% reduction in tumor mass, a 20% reduction in tumor mass, a 30% reduction in tumor mass, a 40% reduction in tumor mass, a 50% reduction in tumor mass, a 60% reduction in tumor mass, a 70% reduction in tumor mass, an 80% reduction in tumor mass, a 90% reduction in tumor mass, or a 100% reduction in tumor mass following initiation of treatment.

28. The method of claim 1 , wherein the tumor exhibits a 10% reduction in tumor mass following initiation of treatment.

29. The method of claim 1 , wherein the tumor exhibits a 20% reduction in tumor mass following initiation of treatment.

30. The method of claim 1 , wherein the tumor exhibits a 50% reduction in tumor mass following initiation of treatment.

31. The method of claim 1 , wherein the tumor exhibits a 50%, 60%, 70%, 80% or 90% reduction in tumor mass following initiation of treatment.