# US 12,595,517 B2 · Method to treat and stratify a patient suffering from a cancer > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 12,595,517 B2 - Document ID: US12595517B2 - Status: Granted - Kind: B2 - Application number: 18/245,067 - Filed: 2021-09-13 - Published: 2023-11-09 - Granted: 2026-04-07 - Earliest claimed: 2020-09-14 - Assignees: Inserm (Institute National De La Sante Et De La Recherche Medicale); Institute De CancéRologie De L'ouest; Nantes Universite - Applicants: Inserm (Institut National De La Santé Et De La Recherche MéDicale); Institut De CancéRologie De L'ouest; Nantes Université - Inventors: Pierre-François Cartron; Gwenola Bougras-Cartron - Web page: https://patentgrep.com/patent/US12595517B2 ## CPC - C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575) - A61K 31/496: Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin - A61P 35/00: Antineoplastic agents - C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism - C12Q 2600/158: Expression markers - C12Q 2600/178: miRNA, siRNA or ncRNA - C12Q: MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS (immunoassay G01N33/53); COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES - 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 present invention relates to the stratification and treatment of patients suffering of cancer. Due to the fact that anti-PD1 therapy targets lymphocytes and the efficiency of anti-cancer therapy is measured by the impact on the tumor cells, the inventors postulated that studying the molecular mechanisms of resistance of anti-PD1 therapy should take into consideration existing intercellular communication between lymphocytes and tumor cells. As exosomes are the carriers for the intercellular transfer of the miRNA responsible of chemoresistance, they herein investigated whether exposure of T cells to anti-PD1 therapy might promote the expression of exosomal miRNA (exomiR) causing the chemoresistance of cancer cells. Surprisingly, they found that anti-PD1 exposure of T-cell promotes an enrichment of exosomal miRNA-4315. They also noted that exosomal miRNA-4315 induced a phenomenon of apopto-resistance to conventional chemotherapies in cancer cells receiving exosomal miRNA-4315. At molecular level, they discern that the apopto-resistance phenomenon was associated with the miRNA-4315-mediated down-regulation of Bim, a pro-apoptotic protein. In cellular and mice models, they observed that the BH3 mimetic agent ABT263 circumvented this resistance. Thus, the invention relates to methods of stratification using exosomal miRNA-4315 and method of treatment of patients suffering of cancer using BH3 mimetic agent. ## Claims ### Claim 1 A method of identifying a patient having or at risk of having or developing a resistance to anti-PD-1 therapy and treating the patient, comprising i) determining the expression level of exosomal miRNA-4315 in a sample from said patient, ii) comparing said expression level with a predetermined reference value iii) determining that the expression level of the exosomal miRNA-4315 is less than the predetermined reference value; and iv) treating, with the anti-PD-1 therapy, the patient determined to have an expression level of the exosomal miRNA-4315 that is less than the predetermined reference value. ### Claim 2 (depends on 1) The method according to claim 1, wherein the anti-PD-1 therapy is nivolumab, pembrolizumab or cemiplimab. ### Claim 3 (depends on 1) The method according to claim 1, wherein the sample is blood, plasma, serum, T cell-derived exosomes or a cancer biopsy. ### Claim 4 (depends on 1) The method according to claim 1, wherein the patient receives simultaneously, separately or in a sequential manner a standard chemotherapy with the anti-PD-1 therapy. ### Claim 5 (depends on 4) The method according to claim 4, wherein the standard chemotherapy is oxaliplatin, cisplatin, temozolomide, cyclophosphamide, doxorubicin or paclitaxel. ### Claim 6 A method of treating cancer in a patient in need thereof, comprising, determining an expression level of exosomal miRNA-4315 in a sample from said patient, comparing said expression level with a predetermined reference value, determining that the expression level of the exosomal miRNA-4315 is higher than the predetermined reference value, and treating, with a BH3 mimetic agent, the patient determined to have an expression level of the exosomal miRNA-4315 that is higher than the predetermined reference value. ### Claim 7 (depends on 6) The method of claim 6, wherein the patient is resistant to an anti-PD-1 therapy. ### Claim 8 (depends on 6) The method according to claim 6, wherein the BH3 mimetic agent is selected from the group consisting of: ABT-737, venetoclax (ABT-199) and navitoclax (ABT-263). ### Claim 9 (depends on 1) The method according to claim 1, wherein the cancer is a glioblastoma (GBM), a lung cancer, a breast cancer or an ovarian cancer. ### Claim 10 (depends on 6) The method according to claim 6, wherein the cancer is a glioblastoma (GBM), a lung cancer, a breast cancer or an ovarian cancer.