# US 12,109,177 B2 · Neutrophil suppression as preconditioning to increase oncolytic bacterial therapy

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- Number: US 12,109,177 B2
- Document ID: US12109177B2
- Status: Granted
- Kind: B2
- Application number: 18/085,467
- Filed: 2022-12-20
- Published: 2023-06-29
- Granted: 2024-10-08
- Earliest claimed: 2021-12-28
- Assignees: The Johns Hopkins University
- Applicants: The Johns Hopkins University
- Inventors: Renyuan Bai; Verena Staedtke
- Web page: https://patentgrep.com/patent/US12109177B2

## CPC

- A61K 31/133: having hydroxy groups, e.g. sphingosine
- A61K 31/535: having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
- A61K 31/664: Amides of phosphorus acids
- A61K 31/675: having nitrogen as a ring hetero atom, e.g. pyridoxal phosphate
- A61K 35/74: Bacteria (therapeutic use of a bacterial protein A61K38/00)
- A61K 35/742: Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- 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

## Abstract

Provided herein are methods for increasing the therapeutic efficiency of oncolytic bacterial therapeutics. Bacterial oncolytic therapies, especially the ones targeting tumor hypoxia such as C. novyi-NT, often encounter incomplete tumor clearance in less hypoxic tumoral areas and severe inflammatory reactions. In this study, we explored immune-modulating preconditioning to suppress the host neutrophils and significantly enhanced the antitumor efficacy of C. novyi-NT in animal models, including an orthotopic brain tumor model in rabbits. The optimized preconditioning agent, hydroxyurea, is clinically approved and C. novyi-NT has demonstrated manageable safety and promising antitumor responses in clinical trials. Thus, the proposed preconditioning of neutrophil suppression is readily translatable to patients undergoing C. novyi-NT trials or other oncolytic biologic therapies and could improve outcome.

## Claims

### Claim 1

A method of treating a solid tumor in a subject comprising:
(a) administering to the subject at least one immunoregulatory compound selected from at least one of an anti-neutrophil antibody, hydroxyurea, or cyclophosphamide; and
(b) administering at least one anaerobic species of bacteria,
wherein the at least one immunoregulatory compound is administered prior to administering the anaerobic species of bacteria,
thereby treating the solid tumor in the subject.

### Claim 2 (depends on 1)

The method of claim 1, wherein the solid tumor is brain, colon, breast, prostate, liver, kidney, lung, esophagus, head and neck, ovary, cervix, stomach, colon, rectum, bladder, uterus, testis, or pancreatic cancer.

### Claim 3 (depends on 2)

The method of claim 2, wherein the solid tumor is brain cancer.

### Claim 4 (depends on 1)

The method of claim 1, further comprising administering prednisone, methylprednisolone, dexamethasone, colchicine, hydroxychloroquine, sulfasalazine, infliximab, adalimumab, golimumab, etanercept, certolizumab, tocilizumab, sarilumab, eculizumab, secukinumab, ixekizumab, brodalumab, guselkumab, or dapsone with the immunomodulatory compound.

### Claim 5 (depends on 1)

The method of claim 1, wherein the immunoregulatory compound is administered to the subject from about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days prior to administering the anaerobic species of bacteria.

### Claim 6 (depends on 5)

The method of claim 5, wherein the immunoregulatory compound is administered to the subject at a reduced dose for about 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 days after administering the anaerobic species of bacteria.

### Claim 7 (depends on 1)

The method of claim 1, wherein the immunoregulatory compound is cyclophosphamide or hydroxyurea.

### Claim 8 (depends on 7)

The method of claim 7, wherein the cyclophosphamide or hydroxyurea is administered at a dose of about 0.1 mg/kg, 1 mg/kg, 10 mg/kg, 20 mg/kg, 25 mg/kg, 50 mg/kg, 75 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 200 mg/kg, 300 mg/kg, 400 mg/kg or 500 mg/kg per day.

### Claim 9 (depends on 7)

The method of claim 7, wherein the cyclophosphamide is administered with at least one antineoplastic detoxifying agent.

### Claim 10 (depends on 1)

The method of claim 1, wherein the anti-neutrophil antibody is an anti-Ly6G antibody.

### Claim 11 (depends on 1)

The method of claim 1, wherein the immunoregulatory compound is administered to the subject from about 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48, 50, 52, 54, 56, 58, 60, 62, 64, 66, 68, 70, or 72 hours prior to administering the anaerobic species of bacteria.