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; and

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

2 . The method of claim 1 , 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.

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

4 . The method of claims 1 - 3 , wherein the anti-PD1 antibody is a humanized antibody.

5 . The method of claims 1 - 4 , wherein the anti-PD1 antibody is pembrolizumab.

6 . The method of claims 1 - 5 , wherein the oncolytic adenovirus is delivered intratumorally.

7 . The method of claim 6 , wherein the oncolytic adenovirus is delivered via cannula or needle.

8 . The method of claims 1 - 7 , 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.

9 . The method of claims 1 - 8 , wherein the anti-PD1 antibody is delivered by intravenous infusion.

10 . The method of claims 1 - 9 , wherein the anti-PD1 antibody is delivered at 200 mg per dose.

11 . The method of claim 10 , wherein the dose is administered over 30 minutes.

12 . The method of claims 1 - 11 , wherein a single dose of the oncolytic adenovirus is provided prior to three consecutive doses of the anti-PD1 antibody.

13 . The method of claim 12 , wherein the time between oncolytic adenovirus administration and the first administration of the anti-PD1 antibody is about 7-9 days.

14 . The method of claims 12 - 13 , wherein the time between sequential administrations of the anti-PD1 antibody is about three weeks.

15 . The method of claims 1 - 14 , further comprising administering to the subject one or more of a steroid, an anticonvulsant or an antibody that inhibits vascular endothelial growth factor A.

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

17 . The method of claims 1 - 16 , wherein said subject is evaluated for one of more of overall survival, tumor response, clinical benefit rate, Karnofsky performance status, neurologic status, cytokine levels, lymphocyte levels, or a biomarker.

18 . The method of claim 17 , wherein said biomarker is PD-1 level or PDL-1 level.

19 . The method of claim 18 , wherein tumor response is measured by MRI.

20 . The method of claims 1 - 19 , further comprising stereotactically-guided biopsy of the brain tumor.

21 . The method of claims 1 - 20 , wherein the brain tumor is glioblastoma multiforme.

22 . The method of claims 1 - 20 , wherein the brain tumor is gliosarcoma.

23 . The method of claims 1 - 22 , 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.

24 . The method of claims 1 - 22 , 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.

25 . The method of claims 1 - 22 , 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.

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

27 . The method of claims 1 - 22 , wherein there is a statistically measurable clinical benefit.

28 . The method of claims 1 - 27 , wherein the subject exhibits recurrent or progressive brain tumor following previous treatment.

29 . The method of claims 1 - 28 , wherein the previous treatment was chemotherapy, radiotherapy, or antibody therapy.

30 . The method of claims 1 - 29 , wherein the subject is a human.

31 . A composition comprising:

(a) an oncolytic adenovirus; and

(b) an anti-PD-1 antibody.

32 . The composition of claim 31 , wherein the oncolytic adenovirus is an adenovirus serotype 5 strain, and/or wherein the oncolytic adenovirus is selectively replication competent in cells defective in the Rb/p16 tumor suppressor pathway, and/or wherein the oncolytic adenovirus comprises a deletion of the 24 nucleotides encoding amino acids 122 to 129 of the adenoviral E1A protein, and/or wherein the oncolytic adenovirus comprises an integrin binding RGD-4C motif.

33 . The composition of claims 31 - 32 , wherein the oncolytic adenovirus is DNX-2401.

34 . The composition of claims 31 - 33 , wherein the anti-PD1 antibody is a humanized antibody.

35 . The composition of claims 31 - 34 , wherein the anti-PD1 antibody is pembrolizumab.

36 . The composition of claims 31 - 35 , wherein the composition is formulated for intratumoral delivery.

37 . The composition of claims 31 - 35 , wherein the composition is formulated for intravenous infusion.

38 . The composition of claims 31 - 37 , wherein the oncolytic adenovirus is comprised in a unit dose of 5×10 8 viral particles per dose, 5×10 9 viral particles per dose, or 5×10 10 viral particles per dose.

39 . The composition of claims 31 - 38 , wherein the anti-PD1 antibody is comprised in a unit dose of 200 mg.

40 . The composition of claims 31 - 39 , further comprising one or more of a steroid, an anticonvulsant or an antibody that inhibits vascular endothelial growth factor A.

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

42 . The composition of claim 41 , wherein the oncolytic adenovirus is DNX-2401.

43 . The composition of claims 41 - 42 , wherein the oncolytic adenovirus is comprised in a unit dose of 5×10 8 viral particles per dose.

44 . The composition of claims 41 - 42 , wherein the oncolytic adenovirus is comprised in a unit dose of 5×10 9 viral particles per dose.

45 . The composition of claims 41 - 42 , wherein the oncolytic adenovirus is comprised in a unit dose of 5×10 10 viral particles per dose.