# US 12,214,001 B2 · Cancer therapy

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- Number: US 12,214,001 B2
- Document ID: US12214001B2
- Status: Granted
- Kind: B2
- Application number: 18/076,133
- Filed: 2022-12-06
- Published: 2023-05-11
- Granted: 2025-02-04
- Earliest claimed: 2020-06-10
- Assignees: Prokarium Limited
- Applicants: Prokarium Limited
- Inventors: Livija Deban; Hyam Levitsky
- Web page: https://patentgrep.com/patent/US12214001B2

## CPC

- A61K 35/74: Bacteria (therapeutic use of a bacterial protein A61K38/00)
- A61K 40/11: T-cells, e.g. tumour infiltrating lymphocytes [TIL] or regulatory T [Treg] cells; Lymphokine-activated killer [LAK] cells
- A61K 40/31: Chimeric antigen receptors [CAR]
- A61K 40/42: Cancer antigens
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61P 35/02: specific for leukemia
- A61P 37/02: Immunomodulators
- A61K 9/0053: {Mouth and digestive tract, i.e. intraoral and peroral administration}
- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 2039/505: {comprising antibodies}
- C07K 16/2827: {against B7 molecules, e.g. CD80, CD86}
- Y02A 50/30: Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
- 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)
- Y02A: TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE

## Abstract

The present invention relates to the field of cancer therapy. In particular, the present invention relates to a live attenuated Gram-negative bacterium for use in the treatment, reduction, inhibition or control of a neoplastic disease in a subject undergoing or intended to undergo immunotherapy with a checkpoint inhibitor therapy, an adoptive T cell therapy and/or an allogeneic or an autologous CAR-T therapy simultaneously, separately or sequentially with the administration of the live attenuated Gram-negative bacterium.

## Claims

### Claim 1

A method of treating, reducing, inhibiting or controlling a neoplastic disease in a subject undergoing or intended to undergo a checkpoint inhibitor therapy, an adoptive cell therapy and/or an allogenic or autologous CAR-T therapy, comprising administering simultaneously, separately or sequentially a live attenuated Gram-negative bacterium, wherein the live attenuated Gram-negative bacterium is orally administered, subcutaneously administered, intradermally administered or intramuscularly administered, wherein said live attenuated Gram-negative bacterium is non-recombinant or does not comprise eukaryotic heterologous DNA encoding a therapeutic protein.

### Claim 2 (depends on 1)

The method of claim 1, wherein the live attenuated Gram-negative bacterium is to be administered in a first treatment phase and the checkpoint inhibitor therapy, the adoptive T cell therapy or the allogeneic or the autologous CAR-T therapy is to be administered in a second treatment phase.

### Claim 3 (depends on 1)

The method of claim 1, wherein the live attenuated Gram-negative bacterium is a Salmonella spp.

### Claim 4 (depends on 1)

The method of claim 1, wherein the live attenuated Gram-negative bacterium is Salmonella enterica.

### Claim 5 (depends on 1)

The method of claim 1, wherein the live attenuated Gram-negative bacterium is Salmonella enterica serovar Typhi or wherein the live attenuated Gram-negative bacterium is Salmonella enterica serovar Typhimurium.

### Claim 6 (depends on 1)

The method of claim 1, wherein the live attenuated Gram-negative bacterium is a genetically engineered non-natural bacterium.

### Claim 7 (depends on 1)

The method of claim 1, wherein the live attenuated Gram-negative bacterium is selected from the group consisting of Ty21a, CVD 908-htrA, CVD 909, Ty800, M01ZH09, x9633, x9640, x8444, DTY88, ZH9PA, MD58, WT05, ZH26, SL7838, SL7207, VNP20009 and A1-R.

### Claim 8 (depends on 1)

The method of claim 1, wherein the checkpoint inhibitor is a blocking agent directed against CTLA-4, PD-1, PD-L1, LAG-3, TIM-3, BTLA, TIGIT, VISTA or any combinations thereof.

### Claim 9 (depends on 8)

The method of claim 8, wherein the checkpoint inhibitor is a blocking agent directed against CTLA-4, PD-1 or PD-L1.

### Claim 10 (depends on 1)

The method of claim 1, wherein the adoptive cell therapy is a tumour-infiltrating lymphocyte (TIL) therapy, engineered T-cell receptor (TCR) therapy and/or natural killer (NK) cell therapy.

### Claim 11 (depends on 1)

The method of claim 1, wherein the neoplastic disease is associated with a solid tumour or haematological malignancy.

### Claim 12 (depends on 1)

The method of claim 1, wherein the neoplastic disease is associated with a cancer selected from prostate cancer, liver cancer, renal cancer, lung cancer, breast cancer, colorectal cancer, bladder cancer, pancreatic cancer, brain cancer, hepatocellular carcinoma, lymphoma, leukaemia, gastric cancer, cervical cancer, ovarian cancer, thyroid cancer, melanoma, carcinoma, head and neck cancer, skin cancer or sarcoma.

### Claim 13 (depends on 12)

The method of claim 12, wherein the neoplastic disease is associated with a cancer selected from lung cancer, bladder cancer, gastric cancer, ovarian cancer, colorectal cancer, head and neck cancer, melanoma, renal cancer or breast cancer.

### Claim 14 (depends on 1)

The method of claim 1, wherein the live attenuated Gram-negative bacterium is orally administered.

### Claim 15 (depends on 1)

The method of claim 1, wherein the live attenuated Gram-negative bacterium is administered in a first treatment phase and the checkpoint inhibitor therapy, adoptive T cell therapy and/or the allogeneic or autologous CAR-T therapy are administered in a second treatment phase.

### Claim 16 (depends on 2)

The method of claim 2, wherein the first treatment phase and second treatment phase are administered at least one week apart.

### Claim 17 (depends on 2)

The method of claim 2, wherein the first treatment phase and second treatment phase are administered two weeks apart.

### Claim 18 (depends on 1)

The method of claim 1, wherein said live attenuated Gram-negative bacterium generates a systemic immune response in the subject.

### Claim 19 (depends on 18)

The method of claim 18, wherein the systemic immune response results in an increase in the activation and/or maturation of myeloid cells.

### Claim 20 (depends on 11)

The method of claim 11, wherein the neoplastic disease is associated with a solid tumour.