Combination therapy for treatment of brain cancers

Abstract

Methods of treating a subject having a brain tumor comprising (a) administering an oncolytic virus and (b) administering a therapeutic antibody to said subject.

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.