# US 2013/0156790 A1 · Compounds and uses thereof to induce an immunogenic cancer cell death in a subject > Agents: this data is available as JSON from the patentgrep API and MCP server — see https://patentgrep.com/llms.txt - Number: US 2013/0156790 A1 - Document ID: US20130156790A1 - Status: Published application - Kind: A1 - Application number: 13/772,944 - Filed: 2013-02-21 - Published: 2013-06-20 - Earliest claimed: 2010-04-22 - Assignees: Institut Gustave Roussy - Inventors: LAURENCE ZITVOGEL; GUIDO KROEMER - Web page: https://patentgrep.com/patent/US20130156790A1 ## CPC - C12Q 1/6886: for cancer (immunoassay for cancer G01N33/575) - A61N 5/10: X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy (A61N5/01 takes precedence) - A61P 35/00: Antineoplastic agents - A61N 2005/1098: {Enhancing the effect of the particle by an injected agent or implanted device} - C12Q 2600/106: Pharmacogenomics, i.e. genetic variability in individual responses to drugs and drug metabolism - C12Q 2600/158: Expression markers - 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 - A61N: ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY (measurement of bioelectric currents A61B; surgical instruments, devices or methods for transferring non-mechanical forms of energy to or from the body A61B18/00; anaesthetic apparatus in general A61M; incandescent lamps H01K; infrared radiators for heating H05B) - A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS ## Abstract The present invention relates to the fields of genetics, immunology and medicine. The present invention more specifically relates to in vitro or ex vivo methods for determining the susceptibility to a cancer treatment of a subject having a tumour. These methods comprise a step of determining the ability of the treatment, of the subject and/or of the tumour to induce an anticancer immune response, the inability of at least one of the treatment, the subject and the tumor to induce an anticancer immune response being indicative of a resistance of the subject to the therapeutic treatment of cancer. Inventors in particular identify genes specific of a human subject or of cancerous cells which can be used to predict or assess the sensitivity of a subject to a treatment of cancer. The invention also relates to particular compounds capable of activating or enhancing the immune system of a particular subject, when the subject is exposed to a therapeutic treatment of cancer or before such an exposition. It further relates to uses of such compounds, in particular to prepare a pharmaceutical composition to allow or improve the efficiency of a therapy of cancer in a subject in need thereof. The present invention in addition provides kits, methods for selecting a compound of interest, as well as pharmaceutical compositions and uses thereof. ## Claims ### Claim 1 An in vitro method of assessing the sensitivity of a subject having a tumor to a treatment of cancer, which method comprises a step of determining the ability of the tumor to induce an anticancer immune response, said step comprising verifying the expression by tumor cells of nuclear HMGB1, wherein the absence of nuclear HMGB1 in tumor cells is indicative of the inability of the tumor to induce an anticancer immune response and wherein the inability of the tumor to induce an anticancer immune response is indicative of a resistance of the subject to the treatment of cancer, and wherein, on the contrary, the presence of nuclear HMGB1 in tumor cells is indicative of the ability of the tumor to induce an anticancer immune response and wherein the ability of the tumor to induce an anticancer immune response is indicative of the subject's sensitivity to the treatment of cancer. ### Claim 2 (depends on 1) The method according to claim 1, wherein the treatment of cancer is a conventional immunogenic treatment of cancer selected from a chemotherapy using a drug selected from an anthracyclin, a platin, an oxaliplatin, a taxane, a cyclophosphamide and an antimotic agent; or radiotherapy. ### Claim 3 (depends on 1) The method according to claim 1, wherein the subject has been treated for cancer or is undergoing the therapeutic treatment of cancer. ### Claim 4 (depends on 1) The method according to claim 1, wherein the step of determining the ability of the tumor to induce an anticancer immune response further comprises verifying the expression by tumor cells of cytosolic microtubule-associated protein 1 light chain 3 (LC3), in particular of LC3-II, wherein the absence of cytosolic LC3 in tumor cells is indicative of the inability of the tumor to induce an anticancer immune response, and wherein, on the contrary, the presence of cytosolic LC3 in tumor cells is indicative of the ability of the tumor to induce an anticancer immune response. ### Claim 5 (depends on 1) The method according to claim 1, wherein the step of determining the ability of the tumor to induce an anticancer immune response further comprises verifying the expression by tumor cells of ecto-nucleoside-triphosphate-diphosphohydrolase (CD39) and/or of the ectonucleotidase CD73, and wherein the presence of CD39 and/or CD73 is indicative of the inability of the tumor to induce an anticancer immune response. ### Claim 6 (depends on 4) The method according to claim 4, wherein the step of determining the ability of the tumor to induce an anticancer immune response further comprises verifying the expression by tumor cells of ecto-nucleoside-triphosphate-diphosphohydrolase (CD39) and/or of the ectonucleotidase CD73, and wherein the presence of CD39 and/or CD73 is indicative of the inability of the tumor to induce an anticancer immune response. ### Claim 7 (depends on 4) The method according to claim 4, wherein the verification is performed on a sample of tumor cells, the detection of cytosolic LC3 in less than 10% of the tumor cells of said sample revealing the absence of LC3, or the presence of CD39 or CD73 in at least 10% cells of the tumor cells revealing an abnormal overexpression of CD39 or CD73 in said tumor cells. ### Claim 8 (depends on 5) The method according to claim 5, wherein the verification is performed on a sample of tumor cells, the detection of cytosolic LC3 in less than 10% of the tumor cells of said sample revealing the absence of LC3, or the presence of CD39 or CD73 in at least 10% cells of the tumor cells revealing an abnormal overexpression of CD39 or CD73 in said tumor cells. ### Claim 9 (depends on 1) The method according to claim 1, wherein cancer is selected from breast cancer, in particular advanced or metatstatic breast cancer; colon cancer; sarcoma; leukemia; ovarian cancer; testicular cancer; brain cancer; head and neck cancer, stomach cancer; or pancreatic cancer. ### Claim 10 (depends on 1) The method of claim 1, said method further comprising treating a subject identified as resistant to said conventional immunogenic treatment of cancer with a drug selected from dendrophilin, an anti-CD39 antibody, an anti-CD73 antibody, and any combination thereof, in combination with a conventional immunogenic treatment of cancer selected from a chemotherapy using a drug selected from using a drug selected from an anthracyclin, a platin, a taxane, a cyclophosphamide and an antimotic agent; and radiotherapy. ### Claim 11 A method of selecting an optimal therapeutic treatment of cancer in a subject having a tumor, said method comprising assessing the sensitivity of the subject to a first treatment of cancer and, if the subject is resistant to said first treatment of cancer, a step of selecting (i) a product allowing or enhancing the secretion of HMGB1 and/or promoting ATP release (ii) a product promoting activation of the TLR4/myd88 pathway, or able to bypass said pathway, (iii) a product stimulating the autophagy machinery, and (iv) any combination thereof, to be used in combination with the first treatment of cancer as the optimal therapeutic treatment of cancer for the subject, wherein said assessing the selectivity of the subject comprises: a) determining the ability of the tumor to induce an anticancer immune response, said step comprising verifying the expression by tumor cells of nuclear HMGB1, wherein the absence of nuclear HMGB1 in tumor cells is indicative of the inability of the tumor to induce an anticancer immune response and wherein the inability of the tumor to induce an anticancer immune response is indicative of a resistance of the subject to the treatment of cancer, and wherein, on the contrary, the presence of nuclear HMGB1 in tumor cells is indicative of the ability of the tumor to induce an anticancer immune response and wherein the ability of the tumor to induce an anticancer immune response is indicative of the subject's sensitivity to the treatment of cancer; b) determining the ability of the tumor to induce an anticancer immune response, said step comprising verifying the expression by tumor cells of nuclear HMGB1, wherein the absence of nuclear HMGB1 in tumor cells is indicative of the inability of the tumor to induce an anticancer immune response and wherein the inability of the tumor to induce an anticancer immune response is indicative of a resistance of the subject to the treatment of cancer, and wherein, on the contrary, the presence of nuclear HMGB1 in tumor cells is indicative of the ability of the tumor to induce an anticancer immune response and wherein the ability of the tumor to induce an anticancer immune response is indicative of the subject's sensitivity to the treatment of cancer, wherein the step of determining the ability of the tumor to induce an anticancer immune response further comprises verifying the expression by tumor cells of cytosolic microtubule-associated protein 1 light chain 3 (LC3), in particular of LC3-II, wherein the absence of cytosolic LC3 in tumor cells is indicative of the inability of the tumor to induce an anticancer immune response, and wherein, on the contrary, the presence of cytosolic LC3 in tumor cells is indicative of the ability of the tumor to induce an anticancer immune response; or c) determining the ability of the tumor to induce an anticancer immune response, said step comprising verifying the expression by tumor cells of nuclear HMGB1, wherein the absence of nuclear HMGB1 in tumor cells is indicative of the inability of the tumor to induce an anticancer immune response and wherein the inability of the tumor to induce an anticancer immune response is indicative of a resistance of the subject to the treatment of cancer, and wherein, on the contrary, the presence of nuclear HMGB1 in tumor cells is indicative of the ability of the tumor to induce an anticancer immune response and wherein the ability of the tumor to induce an anticancer immune response is indicative of the subject's sensitivity to the treatment of cancer, wherein the step of determining the ability of the tumor to induce an anticancer immune response further comprises verifying the expression by tumor cells of ecto-nucleoside-triphosphate-diphosphohydrolase (CD39) and/or of the ectonucleotidase CD73, and wherein the presence of CD39 and/or CD73 is indicative of the inability of the tumor to induce an anticancer immune response. ### Claim 12 (depends on 11) The method according to claim 11, wherein the product capable of promoting activation of the TLR4/myd88 pathway is dendrophilin, in particular dendrophilin S or dendrophilin A. ### Claim 13 (depends on 11) The method according to claim 11, wherein the product stimulating the autophagy machinery is an ecto-ATPase (apyrase) inhibitor selected from an anti-CD39 antibody and an anti-CD73 antibody. ### Claim 14 A therapeutic kit comprising i) at least one drug selected from dendrophilin, ii) an anti-CD39 antibody, and an anti-CD73 antibody; and iii) a drug selected from an anthracyclin, a platin, a taxane, a cyclophosphamide and an antimotic agent. ### Claim 15 A diagnostic kit comprising i) at least one HMGB1 antibody, ii) at least one anti-LC3 antibody, and optionally iii) at least one antibody inhibitor of detecting an ecto-ATPase, preferably selected from an anti-CD39 antibody and an anti-CD73 antibody. ### Claim 16 A method for treating a subject having a tumor, said subject being resistant to chemotherapy using a drug selected from an anthracyclin, a platin, an oxaliplatin, a taxane, a cyclophosphamide and an antimotic agent; or radiotherapy, wherein said method comprises exposing said subject to said chemotherapy or radiotherapy and, simultaneously or subsequently, administering intratumorously, in the tumor bed or systemically dendrophilin, an anti-CD39 antibody, and/or an anti-CD73 antibody to said subject.