# US 11,110,137 B2 · Combination therapy for treatment of brain cancers

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- Number: US 11,110,137 B2
- Document ID: US11110137B2
- Status: Granted
- Kind: B2
- Application number: 16/997,552
- Filed: 2020-08-19
- Published: 2020-12-03
- Granted: 2021-09-07
- Earliest claimed: 2016-11-01
- Assignees: Dnatrix, Inc.
- Applicants: Dnatrix, Inc.
- Inventors: Frank Tufaro; Joanna J. Peterkin
- Web page: https://patentgrep.com/patent/US11110137B2

## CPC

- A61K 35/761: Adenovirus
- A61K 9/0019: {Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner (non-active ingredients are additionally classified in A61K47/00)}
- A61K 9/0085: {Brain, e.g. brain implants; Spinal cord}
- A61K 39/3955: {against proteinaceous materials, e.g. enzymes, hormones, lymphokines}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- C07K 16/2818: {against CD28 or CD152}
- A61K 2039/505: {comprising antibodies}
- A61K 2039/54: {characterised by the route of administration}
- A61K 2039/545: {characterised by the dose, timing or administration schedule}
- C07K 2317/24: containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
- C12N 2710/10321: Viruses as such, e.g. new isolates, mutants or their genomic sequences
- C12N 2710/10332: Use of virus as therapeutic agent, other than vaccine, e.g. as cytolytic agent
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- C12N: MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA (microbiological testing media C12Q1/00)

## 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.

## Claims

### Claim 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.

### Claim 2 (depends on 1)

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

### Claim 3 (depends on 1)

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

### Claim 4 (depends on 3)

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

### Claim 5 (depends on 1)

The method of claim 1, wherein the oncolytic adenovirus is delivered at 5×108 viral particles per dose, 5×109 viral particles per dose, or 5×1010 viral particles per dose.

### Claim 6 (depends on 1)

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

### Claim 7 (depends on 1)

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

### Claim 8 (depends on 1)

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.

### Claim 9 (depends on 8)

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.

### Claim 10 (depends on 8)

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

### Claim 11 (depends on 1)

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.

### Claim 12 (depends on 8)

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.

### Claim 13 (depends on 1)

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.

### Claim 14 (depends on 13)

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

### Claim 15 (depends on 1)

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

### Claim 16 (depends on 1)

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

### Claim 17 (depends on 1)

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

### Claim 18 (depends on 1)

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

### Claim 19 (depends on 1)

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.

### Claim 20 (depends on 1)

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.

### Claim 21 (depends on 1)

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

### Claim 22 (depends on 1)

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

### Claim 23 (depends on 1)

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

### Claim 24 (depends on 1)

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

### Claim 25 (depends on 1)

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

### Claim 26 (depends on 1)

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

### Claim 27 (depends on 1)

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.

### Claim 28 (depends on 1)

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

### Claim 29 (depends on 1)

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

### Claim 30 (depends on 1)

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

### Claim 31 (depends on 1)

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