# US 12,599,662 B2 · Methods and compositions for treating cancers

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- Number: US 12,599,662 B2
- Document ID: US12599662B2
- Status: Granted
- Kind: B2
- Application number: 17/265,580
- Filed: 2019-08-06
- Published: 2021-08-05
- Granted: 2026-04-14
- Earliest claimed: 2018-08-06
- Assignees: Inserm (Institut National De La Sante Et De La Recherche Medicale); Universite Paris-Saclay; Assistance Publique-Hopitaux de Paris; Universite De Paris
- Applicants: Inserm (Institut National De La Santé Et De La Recherche MéDicale); Université Paris-Saclay; Assistance Publique—HôPitaux De Paris; UniversitéDe Paris
- Inventors: Frank Griscelli; Ali Turhan; Annelise Bennaceur Griscelli
- Web page: https://patentgrep.com/patent/US12599662B2

## CPC

- A61K 39/39: characterised by the immunostimulating additives, e.g. chemical adjuvants
- A61K 31/167: having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
- A61K 31/18: Sulfonamides (compounds containing a para-N-benzene-sulfonyl-N- group A61K31/63)
- A61K 31/19: Carboxylic acids, e.g. valproic acid (salicylic acid A61K31/60)
- A61K 31/343: condensed with a carbocyclic ring, e.g. coumaran, bufuralol, befunolol, clobenfurol, amiodarone
- A61K 31/4015: having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
- A61K 31/4045: Indole-alkylamines; Amides thereof, e.g. serotonin, melatonin
- A61K 31/4406: only substituted in position 3, e.g. zimeldine (nicotinic acid A61K31/455)
- A61K 31/506: not condensed and containing further heterocyclic rings
- A61K 31/713: Double-stranded nucleic acids or oligonucleotides
- A61K 40/10: characterised by the cell type used
- A61K 40/4202: {Receptors, cell surface antigens or cell surface determinants}
- A61K 45/06: Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
- A61P 35/00: Antineoplastic agents
- A61K 2039/515: {Animal cells}
- A61K 2039/55511: {Organic adjuvants}
- A61K 2039/55561: {CpG containing adjuvants; Oligonucleotide containing adjuvants}
- A61K 2039/55577: {Saponins; Quil A; QS21; ISCOMS}
- A61K 2239/31: characterized by the route of administration
- A61K 2239/38: characterised by the dose, timing or administration schedule
- A61K 2239/49: Breast
- 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

The invention relates to a method for treating cancers. Many cancers harbour sternness signature to de-differentiate into immature progenitors confer to tumor clones the re-expression of genes from fetal development. Inventors have obtained mice per group which received two boosts of vaccine 7 and 14 days with 2×106 irradiated hESCs cells that were mixed with 3 different adjuvants: 500 μg of TLR3, 50 μg of TLR9 agonist or 50 μg/ml of Quil A® Saponin vaccine adjuvant. After 14 days 5×104 4T1 cells were injected into the mammary fat pad of the mice and Valproic acid added in the drinking water at the dose of 4 mg/ml. They have shown that in contrast to the non-vaccinated mice, the mice vaccinated with hESC combined with a TLR3 agonist have generated the highest reduction of breast tumor volume (p<0.001) compared to the use of a TLR9 agonist or to Quil-A® Saponin vaccine adjuvant. Accordingly, the invention relates to a method for treating a subject suffering from a cancer with i) an agent that induces MHC-I presentation of antigens, ii) a vaccine composition containing an immunogenic element and iii) an adjuvant.

## Claims

### Claim 1

A method for treating a subject suffering from a cancer, comprising administrating simultaneously, separately, or sequentially to the subject a therapeutically effective amount of:
(i) an agent that induces MHC-I presentation of antigens, wherein the agent is a histone deacetylase inhibitor (HDACi);
(ii) a vaccine composition comprising inactivated pluripotent or fetal stem cells, as an immunogenic element; and
(iii) an adjuvant, wherein the adjuvant is an agonist of toll-like receptor (TLR) 3.

### Claim 2 (depends on 1)

The method of claim 1, wherein the vaccine composition comprises inactivated fetal stem cells containing a multiplicity of fetal antigens.

### Claim 3 (depends on 1)

The method of claim 1, wherein the pluripotent or fetal stem cells express one or more antigens also expressed by the cancer cells of the subject.

### Claim 4 (depends on 2)

The method of claim 2, wherein the inactivated fetal stem cells are obtained by a process comprising:
(a) differentiating a population of pluripotent cells along a pathway specific to the subject's cancer;
(b) expanding the differentiated cells, while optionally exposing the differentiated cells to a mutagenic agent to induce mutagenesis;
(c) verifying that at least 70% of the expanded cells express fetal markers;
(d) optionally, verifying that the expanded cells express at least one tumor associated antigen (TAA) or neo-antigen that is present in the subject's cancer cells; and
(e) inactivating the expanded cells to eliminate their ability to divide.

### Claim 5 (depends on 1)

The method of claim 1, wherein the pluripotent stem cells are obtained by a process comprising:
(a) expanding pluripotent cells under conditions that maintain their pluripotency, optionally in the presence of an agent that induces MHC-I presentation of antigens during the expansion; and
(b) exposing the expanded cells to an inactivating agent to inactivate the expanded pluripotent cells while maintaining cell envelope integrity.

### Claim 6 (depends on 1)

The method of claim 1, wherein the histone deacetylase inhibitor is selected from Valproic acid (VPA), Vorinostat, Panobinostat, Givinostat, Belinostat, Levetiracetam, Entinostat, Mocetinostat, Practinostat, Chidamide, Quisinostat, and Abexinostat.

### Claim 7 (depends on 1)

The method of claim 1, wherein the TLR3 agonist is Poly(A:U) or poly(I:C).

### Claim 8 (depends on 1)

The method of claim 1, wherein the vaccine composition containing the immunogenic element and the agonist of TLR 3 is initially administered followed by multiple administrations of the histone deacetylase inhibitor.

### Claim 9 (depends on 1)

The method of claim 1, wherein the cancer is selected from liver cancer, bladder carcinoma, breast carcinoma, cervical carcinoma, cholangiocarcinoma, colorectal carcinoma, gastric sarcoma, glioma, glioblastoma, lung carcinoma, lymphoma, acute lymphoid leukemia, chronic lymphoid leukemia, myeloid leukemias, melanoma, multiple myeloma, osteosarcoma, ovarian carcinoma, pancreatic carcinoma, prostate carcinoma, stomach carcinoma, renal carcinoma, head and neck tumor, hematopoietic malignancies, and RET-mutated endocrine tumors.

### Claim 10 (depends on 1)

The method of claim 1, wherein the cancer is a hormone-dependent cancer.

### Claim 11 (depends on 10)

The method of claim 10, wherein the cancer is selected from a breast cancer, a prostate cancer, a uterus cancer, and an ovary cancer.

### Claim 12 (depends on 9)

The method of claim 9, wherein the RET-mutated endocrine tumor is a medullary thyroid cancer.

### Claim 13 (depends on 4)

The method of claim 4, wherein the pluripotent cells are exposed to the mutagenic agent during expansion.

### Claim 14 (depends on 5)

The method of claim 5, wherein the pluripotent cells are exposed to the mutagenic agent during expansion.

### Claim 15 (depends on 13)

The method of claim 13, wherein the mutagenic agent is N-ethyl-N-nitrosourea (ENU).

### Claim 16 (depends on 14)

The method of claim 14, wherein the mutagenic agent is N-ethyl-N-nitrosourea (ENU).