# US 10,869,926 B2 · Suppression of myeloid derived suppressor cells and immune checkpoint blockade

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- Number: US 10,869,926 B2
- Document ID: US10869926B2
- Status: Granted
- Kind: B2
- Application number: 15/326,186
- Filed: 2015-07-13
- Published: 2017-07-06
- Granted: 2020-12-22
- Earliest claimed: 2014-07-15
- Assignees: The Johns Hopkins University
- Applicants: The Johns Hopkins University
- Inventors: Shibin Zhou; Bert Vogelstein; Kenneth W. Kinzler; KiBem Kim
- Web page: https://patentgrep.com/patent/US10869926B2

## CPC

- A61K 39/39558: {against tumor tissues, cells, antigens}
- A61K 31/437: the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/706: containing six-membered rings with nitrogen as a ring hetero atom
- A61K 35/742: Spore-forming bacteria, e.g. Bacillus coagulans, Bacillus subtilis, clostridium or Lactobacillus sporogenes
- 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 1/00: Drugs for disorders of the alimentary tract or the digestive system
- A61P 15/00: Drugs for genital or sexual disorders (for disorders of sex hormones A61P5/24); Contraceptives
- A61P 31/04: Antibacterial agents
- A61P 31/12: Antivirals
- A61P 35/00: Antineoplastic agents
- A61P 35/04: specific for metastasis
- A61P 43/00: Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
- C07K 16/2818: {against CD28 or CD152}
- A61K 2039/505: {comprising antibodies}
- C07K 2317/34: Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
- C07K 2317/92: Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
- 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)

## Abstract

Impressive responses have been observed in patients treated with checkpoint inhibitory anti-PD-1 or anti-CTLA-4 antibodies. However, immunotherapy against poorly immunogenic cancers remains a challenge. Treatment with both anti-PD-1 and anti-CTLA-4 antibodies were unable to eradicate large, modestly immunogenic CT26 tumors or metastatic 4T1 tumors. However, co-treatment with epigenetic modulating drugs and checkpoint inhibitors markedly improved treatment outcomes, curing more than 80% of them. Functional studies revealed that the primary targets of the epigenetic modulators were myeloid-derived suppressor cells (MDSCs). A PI3K-inhibitor that reduced circulating MDSCs also cured 80% of mice with metastatic 4T1 tumors when combined with immune checkpoint inhibitors. Thus, cancers resistant to immune checkpoint blockade can be cured by eliminating MDSCs.

## Claims

### Claim 1

A method of treating a tumor-bearing mammal, comprising:
administering entinostat which suppresses myeloid derived suppressor cells (MDSCs); and
administering at least two antibodies comprising an anti-PD-1 antibody and an anti-CTLA-4 antibody which block two different immune checkpoints.

### Claim 2 (depends on 1)

The method of claim 1 wherein:
(a) the tumor is not a non-small cell lung cancer (NSLC);
or
(b) spores of Clostridium novyi-NT are also administered to the tumor-bearing mammal.

### Claim 3 (depends on 1)

The method of claim 1 wherein the tumor is selected from the group consisting of colorectal cancer, breast cancer, colorectal cancer metastasis, and breast cancer metastasis.

### Claim 4 (depends on 1)

The method of claim 1 wherein entinostat is administered at a dose which is insufficient alone to inhibit tumor cell growth.