WO2013189287A1 - Utilisation d'interféron dans le traitement/la prévention de tumeurs résistantes à la thérapie anti-tumorale classique - Google Patents

Utilisation d'interféron dans le traitement/la prévention de tumeurs résistantes à la thérapie anti-tumorale classique Download PDF

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WO2013189287A1
WO2013189287A1 PCT/CN2013/077453 CN2013077453W WO2013189287A1 WO 2013189287 A1 WO2013189287 A1 WO 2013189287A1 CN 2013077453 W CN2013077453 W CN 2013077453W WO 2013189287 A1 WO2013189287 A1 WO 2013189287A1
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tumor
interferon
ifn
cells
tumors
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PCT/CN2013/077453
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傅阳心
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苏州丁孚靶点生物技术有限公司
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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/19—Cytokines; Lymphokines; Interferons
    • A61K38/21—Interferons [IFN]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61N—ELECTROTHERAPY; MAGNETOTHERAPY; RADIATION THERAPY; ULTRASOUND THERAPY
    • A61N5/00—Radiation therapy
    • A61N5/10—X-ray therapy; Gamma-ray therapy; Particle-irradiation therapy
    • A61N2005/1092—Details
    • A61N2005/1098—Enhancing the effect of the particle by an injected agent or implanted device
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to the treatment and prevention of tumors, in particular cancers, in particular, the use of interferon (IFN) in the treatment and/or prevention of tumors which are resistant to conventional anti-tumor therapies and/or Use in conjunction with other anti-tumor therapies, and related products and methods.
  • IFN interferon
  • cytotoxicity of many conventionally used cancer therapies for cancer cells is produced by inducing lethal DNA damage.
  • These commonly used cancer therapies are, for example, radiation therapy (RT), certain chemotherapy (e.g., using antibodies against tumor cells), and the like.
  • RT radiation therapy
  • certain chemotherapy e.g., using antibodies against tumor cells
  • tumors have been found to be unresponsive or poorly responsive to these conventional anti-tumor therapies.
  • there is still a lack of effective means to treat/prevent tumors that are resistant to conventional anti-tumor therapies such as radiation therapy, chemotherapy, and the like.
  • Type I interferons are a family of cytokines that are commonly known for their function in antiviral responses. However, in tumor systems, the function of type I IFN is less studied and characterized. Some evidence suggests that type I IFN may play a role in controlling tumor growth. In particular, early studies using IFN- ⁇ / ⁇ neutralizing antisera showed that type I IFN can limit the growth of transplantable tumors (Gresser et al., 1983). In addition, complete deletion of type I IFN signaling resulted in faster tumor growth and increased mortality in several synergistic transplantable tumor models, including B16 melanoma (Picaud et al., 2002). These studies have demonstrated the importance of type I IFN.
  • type I IFN type II IFN
  • the Cancer Immunology Editor is a process in which the immune system inhibits tumor growth and shapes tumor immunogenicity. Recent studies have shown that type I IFN is required to elicit an anti-tumor response and that the role of type I IFN is differentiated in time from the effect of type II IFN (i.e., IFN- ⁇ ) during cancer immunoediting.
  • type II IFN i.e., IFN- ⁇
  • DC dendritic cells
  • CD8 a (+) DC are functionally related targets for endogenous type I IFN (Diamond et al., 2011). Spontaneous T cell initiation often occurs in response to growing tumors. However, the intrinsic immune mechanisms that promote natural anti-tumor T cell responses have not been identified.
  • type I interferon IFN
  • T cell markers in metastatic tumor tissues.
  • IFN type I interferon
  • mice after tumor transplantation, it was produced by CDllc (+) cells, whereas tumor-induced T cell priming was defective in mice lacking IFN- ⁇ / P R or Statl.
  • host type I IFN is critical for intrinsic immune recognition of growing tumors by signaling on CD8 a (+) DC (Fuertes et al., 2011).
  • the cytotoxicity of many conventionally used anti-tumor therapies for cancer cells is produced by inducing lethal DNA damage.
  • the inventors of the present invention have found that an excess of host DNA can induce the production of IFN, which is a cascade of intrinsic immunity and adaptive immunity, thereby causing tumor regression.
  • IFN is a cascade of intrinsic immunity and adaptive immunity, thereby causing tumor regression.
  • tumor cells or tumors (or hosts) that lack IFN or its associated signaling the immune cascade required to regress tumors cannot be produced, resulting in resistance to conventional anti-tumor immunotherapy.
  • interferon eg, type I interferon (IFN)
  • IFN type I interferon
  • the inventors of the present invention have also discovered that IFN is required to cross-prime T cells, thereby allowing for frequent t-therapy or chemotherapy by sputum IFN. Resistant tumors resolve.
  • IFN-[beta] exogenous type I IFN
  • IFN-[R] exogenous type I IFN
  • the application further develops an antibody-based system to target the delivery of type I IFN to tumor tissues, causing both innate and adaptive immunity to attack the tumor.
  • type I IFN in tumor growth control is described herein, and in a specific embodiment, this is mediated by antibody-based IFN fusion protein delivery in a sputum cell dependent manner.
  • the enhanced cross-initiation ability of tumor invasive DCs is not attributable to the mature state or elevated expression of conventional costimulatory molecules, but rather to the local production of type I IFN.
  • local type I IFN delivery using a clinically relevant adenoviral vector encoding A ⁇ can mediate complete tumor rejection in a CD8 + T cell dependent manner.
  • the results of the present invention support the positive role of type I IFN in producing a tumor-specific CD8+ T cell response produced by IFN (i.e., Ab-IFN) linked to an anti-tumor antibody.
  • One aspect of the invention relates to the use of an interferon, preferably a type I interferon, in particular IFN- ⁇ , a fragment thereof or a functional variant thereof for the preparation of a medicament, wherein the medicament
  • tumors that are resistant to conventional anti-tumor therapies (e.g., radiation therapy, chemotherapy); and/or
  • the conventional therapy induces a tumor-specific adaptive immune response; and wherein the interferon, a fragment thereof or a functional variant thereof is capable of stimulating the production of an anti-tumor cytotoxic sputum lymphocyte.
  • the conventional anti-tumor therapy is radiation therapy. More specifically, it is X-ray radiation, and the dose of the radiation may be, for example, 1 - 5 Gy (for example, 1 Gy, 2 Gy, 3 Gy, 4 Gy, 5 Gy), 10 Gy, 15 Gy, 20 Gy, 25 Gy, 30 Gy or higher; The radiation is for 1 day or at least two days, such as 3 days, 4 days, 5 days or more Long.
  • the interferon, fragment thereof or a functional variant thereof is contained in a viral vector, for example, an adenovirus; an adeno-associated virus; a retrovirus, such as murine mololo Leukemia virus; mouse Harvey sarcoma virus; murine mammary tumor virus; Rous sarcoma virus; SV40-type virus; polyoma virus; Epstein-Barr virus; papilloma virus; disease virus; vaccinia virus; poliovirus; And an RNA virus such as a retrovirus; preferably, the viral vector is an adenoviral vector.
  • a retrovirus such as murine mololo Leukemia virus; mouse Harvey sarcoma virus; murine mammary tumor virus; Rous sarcoma virus; SV40-type virus; polyoma virus; Epstein-Barr virus; papilloma virus; disease virus; vaccinia virus; poliovirus; And an RNA virus such as a retrovirus;
  • the interferon, fragment thereof or a functional variant thereof is linked to a targeting moiety (eg, an antibody) that binds to a tumor associated antigen, wherein the targeting moiety and the interferon, fragment thereof Or a functional variant thereof is directly linked (for example as a fusion protein) or linked by a linker.
  • a targeting moiety eg, an antibody
  • the interferon, fragment thereof Or a functional variant thereof is directly linked (for example as a fusion protein) or linked by a linker.
  • the tumor associated antigen is EGFR
  • the targeting moiety is an anti-EGFR antibody
  • the tumor is a tumor that expresses EGFR.
  • the tumor is a malignant tumor, such as a malignant solid tumor, including but not limited to, for example, breast cancer, lung cancer, prostate cancer, colon cancer, skin cancer, head and neck cancer, lymphoma or melanoma.
  • a malignant tumor such as a malignant solid tumor, including but not limited to, for example, breast cancer, lung cancer, prostate cancer, colon cancer, skin cancer, head and neck cancer, lymphoma or melanoma.
  • the medicament of the invention is for use in combination with at least one other anti-tumor therapy, such as radiation therapy (eg, X-rays as described above) Radiation), chemotherapy, etc.
  • the chemotherapy may be a therapy for administering an antibody directed against a tumor-associated antigen; the chemotherapy may also be, for example, administration of a chemotherapeutic agent such as, but not limited to: a pit-based reagent , antimetabolites, cytotoxic antibiotics, doxorubicin, actinomycin D, mitogen, magenta, gentamicin, doxorubicin, tamoxifen, taxol, taxotere, vinca Neobase, vinblastine, vinorelbine, etoposide (VP-16), 5-oxouracil (5FU), cytarabine, cyclophosphamide, thiotepa, methotrexate, camptothecin, Actinomycin D, mitomycin C, c
  • the conventional anti-tumor therapy is radiation therapy
  • the tumor or host carrying the tumor is defective in one or more of the following: 1) interferon (eg, type I interferon, preferably interferon alpha or beta) expression and/or function, particularly interferon expressed by CD45+ hematopoietic cells; 2) expression and/or function of an interferon receptor, wherein the interferon is The body is, for example, an IFNa receptor and/or an IFNP receptor.
  • compositions e.g., a pharmaceutical composition
  • a composition comprising: - an interferon, a fragment thereof, or a functional variant thereof, the interferon, a fragment thereof, or a functional variant thereof, and a tumor-associated antigen Targeting moieties (eg, antibodies) linked, wherein the targeting moiety is directly linked (eg, as a fusion protein) to the interferon, a fragment thereof, or a functional variant thereof, or joined by a linker;
  • the tumor associated antigen is EGFR
  • the targeting moiety is an anti-EGFR antibody
  • the tumor is a tumor expressing EGFR.
  • the targeting moiety e. g., an anti-EGFR antibody
  • forms a fusion protein e.g., by direct ligation
  • the interferon e.g., a fragment thereof, or a functional variant thereof (e.g., A ⁇ ).
  • the invention relates to the use of a composition of the invention as defined above for the preparation of a medicament, wherein the medicament is for the treatment and/or prevention of a tumor, such as a malignant tumor (especially a malignant solid tumor) It includes, for example, breast cancer, lung cancer, prostate cancer, colon cancer, skin cancer, head and neck cancer, lymphoma or melanoma. In a specific embodiment, the tumor is melanoma.
  • a malignant tumor especially a malignant solid tumor
  • the tumor is melanoma.
  • the invention relates to a kit comprising:
  • kits for use in which the kit is used to treat and/or prevent tumors that are resistant to conventional anti-tumor therapies (eg, radiation therapy, chemotherapy); or for use with other anti-tumor therapies (eg, radiation) Therapy, chemotherapy, combined with the treatment and / or prevention of tumors.
  • conventional anti-tumor therapies eg, radiation therapy, chemotherapy
  • other anti-tumor therapies eg, radiation
  • chemotherapy combined with the treatment and / or prevention of tumors.
  • the invention relates to a method of preventing and/or treating a tumor, the method comprising administering to a patient a therapeutically and/or prophylactically effective amount of an interferon, a fragment thereof or a functional change thereof as defined above Or a composition of the invention as defined above.
  • the patient does not respond to conventional anti-tumor therapies (e.g., radiation therapy).
  • the patient is also defective in one or more of the following: 1) expression and/or function of an interferon (eg, type I interferon, preferably interferon alpha or beta), particularly CD45+ An interferon expressed by a hematopoietic cell; 2) an expression and/or function of an interferon receptor, such as an IFNa receptor and/or an IFN receptor.
  • an interferon eg, type I interferon, preferably interferon alpha or beta
  • an interferon expressed by a hematopoietic cell e.g, type I interferon, preferably interferon alpha or beta
  • an interferon expressed by a hematopoietic cell e.g, an interferon expressed by a hematopoietic cell
  • an interferon receptor such as an IFNa receptor and/or an IFN receptor.
  • the prophylactic and/or therapeutic method further comprises administering to the patient simultaneously, sequentially (in any order) or separately at least one other anti-tumor therapy (eg, radiation therapy, administration of antibody chemistry) Therapy, administration of other chemotherapeutic agents, etc.).
  • at least one other anti-tumor therapy eg, radiation therapy, administration of antibody chemistry
  • Therapy administration of other chemotherapeutic agents, etc.
  • FIG. 1 The therapeutic response to RT depends on the host's response to type I IFN.
  • ⁇ mice and ⁇ or IFNaRl 0 bone marrow (BM) Refactoring were stimulated with B16F10 and tumors were allowed to establish for 14 days or the mean volume of tumors was allowed to reach 100 mm3 .
  • C57B1/6 mice or IFNRK0 mice were inoculated with 5xl 0 5 B16-SIY tumor cells. Tumors established for 15 days received 25 Gy of local RT radiation or were untreated.
  • FIG. 4 The anti-tumor effect of ad-IFN-[beta] is immune mediated and depends on sputum cells.
  • Ad-IFN- ⁇ promotes preferential amplification of tumor antigen-specific cells.
  • WT mice bearing 12-day established B16-SIY tumors were subsequently transferred with a mixture of CFSE-labeled 2C Tg T cells and OTI/Thyr Tg T cells.
  • the tumor treated with IFN- ⁇ ad-nul l or the ad- 3xl0 1Q vp. DL and spleen were collected after three days.
  • FIG. 6 Targeting tumors with adenovirus expressing IFN reduces tumor growth.
  • Balb/C mice were inoculated with 5*10 5 TUB0-EGFR cells. Two weeks after the injection, through the ⁇ 14, Mice were treated with intraperitoneal injection at 17 and 20 days with PBS, Ad-nul or Ad-IFNP (1*10 10 vp). Tumor growth was measured twice a week.
  • Anti-EGFR-fusion proteins are effective in controlling primary tumor growth.
  • WT Balb/C mice were inoculated with 5*10 5 TUB0-EGFR cells. Two weeks after the injection, 25 g of anti-EGFR or anti-antigen was administered by intratumoral injection on days 14, 17 and 20
  • Anti-EGFR-IFN beta is effective in controlling EGFR-B16 tumor growth.
  • mice were inoculated with 5*10 5 B16-EGFR-SIY cells. Ten days after the injection, the mice were treated with 254 g of hlg, anti-EGFR or anti-EGFR-IFN ⁇ by intratumoral injection on days 10, 13 and 16. Tumor growth was measured twice a week.
  • B16-EGFR-SIY cells were seeded with WT B6 mice. Ten days after the injection, the mice were treated with 25 g of hlg, anti-EGFR or anti-EGFR-IFN ⁇ by intratumoral injection on days 10, 13 and 16. Depletion of antibody anti-CD4 and anti-CD8 by intraperitoneal administration on days 9, 14, and 19
  • subsequent transfer refers to the transfer of sputum cells to a recipient.
  • tumor site refers to an in vivo or ex vivo location that contains or is suspected of containing tumor cells.
  • the tumor site includes a solid tumor and a location near or adjacent to where the tumor is growing.
  • administering refers to systemic and/or topical administration.
  • systemic administration refers to administration non-locally such that the substance being administered may affect several organs or tissues throughout the body; or such that the administered substance may cross several organs or tissues throughout the body to reach the target site point.
  • systemic administration can cause the therapeutic product to be expressed from the administered vector in more than one tissue or organ, or can cause the therapeutic product to be expressed at the specific site by the administered vector, for example, due to natural tropism. Or due to an operably linked to a tissue-specific promoter element.
  • systemic administration encompasses various forms of administration including, but not limited to, parenteral administration, intravenous administration, intramuscular administration, subcutaneous administration, transdermal administration, oral administration, and the like.
  • topical administration refers to administration at or around a specific site.
  • topical administration encompasses various forms of administration, such as direct injection to a particular site or injection into it (e.g., intratumoral administration).
  • the term "therapeutically and/or prophylactically effective amount” refers to the requirement to achieve a disease or condition for the treatment and/or prophylaxis (eg, a tumor/cancer, eg, for resolving a tumor or reducing the size of a tumor).
  • a disease or condition for the treatment and/or prophylaxis eg, a tumor/cancer, eg, for resolving a tumor or reducing the size of a tumor.
  • the effective amount can be determined for a specific purpose by practice, in a conventional manner.
  • the therapeutically effective amount can be an amount required to achieve a reduction in the number of cancer cells; a reduction in tumor size; inhibition (ie, slowing or halting) infiltration of cancer cells into peripheral organs; inhibition (ie, slowing down) Or stop) tumor metastasis; inhibit tumor growth; and/or alleviate one or more symptoms associated with cancer.
  • antibody encompasses, for example, monoclonal antibodies, polyclonal antibodies, single chain antibodies, antibody fragments (which exhibit the desired biological or immunological activity).
  • immunoglobulin Ig
  • the antibody can specifically target a tumor antigen, such as a surface tumor antigen, such as EGFR, CD4, CD8, and the like.
  • fragment refers to a portion of a biological molecule (eg, a protein, such as an interferon or its encoding nucleic acid) that is capable of effecting a desired biological function, such as inducing expansion of a tumor-specific T cell. increase.
  • a biological molecule eg, a protein, such as an interferon or its encoding nucleic acid
  • the term "functional variant” means that it is modified (eg, mutated, inserted, deleted, fused, conjugated, cross-linked, etc.) to be different from the parent molecule (eg, interferon), but retains its desired biological activity. Variant.
  • Interferons, fragments thereof, or functional variants thereof can be ligated to the targeting moiety by a variety of conventional methods known in the art.
  • the connection can be direct or indirect (eg As in the case of direct ligation, in the case of direct ligation, it can be achieved by the formation of fusion proteins, conjugation or chemical ligation.
  • the ligation forms a fusion protein, it can be achieved, for example, by recombinant techniques or peptide synthesis techniques.
  • the fusion protein may also comprise a linker that does not disrupt the desired properties of the formed product (eg, induces expansion of tumor-specific tau cells).
  • a person skilled in the art can select an appropriate dosage form according to a specific condition, type of disease (e.g., tumor type, stage of development of the tumor, etc.), severity, patient's body, other therapies that may be administered in combination, previously administered therapies, and the like. Mode of administration.
  • cancer refers to a condition that is generally characterized by unregulated cell growth (e.g., in a mammal, such as a human).
  • cancers include, but are not limited to, breast cancer, lung cancer, prostate cancer, colon cancer, cutaneous cancer, head and neck cancer, lymphoma or melanoma, and the like.
  • conventional anti-tumor therapy refers to a therapy that has hitherto been used in the art to treat and/or prevent the production, progression, metastasis, etc. of a tumor, including, but not limited to, radiation therapy (eg, by using X-ray radiation, Radioisotopes, etc.), use of chemotherapeutic agents, use of tumor-specific antibodies, etc.
  • radioactive therapy resistance means that a tumor or tumor cell does not respond to radioactive treatment of a conventional dose and/or a lethal dose (eg, 15 Gy of X-ray radiation for 3 consecutive days), ie, for example with Compared with tumors of the same shape that were not subjected to the radioactive treatment, the size of the tumor subjected to the radioactive treatment was not significantly reduced, the number of tumor cells was not significantly decreased, the tendency of tumor recurrence was not inhibited, and tumor metastasis was not obtained. Control, etc.
  • a lethal dose eg, 15 Gy of X-ray radiation for 3 consecutive days
  • Type I IFN refers to a Type I interferon which includes, for example, IFN ⁇ , IFNp, IFN w, IFN t , IFN d , IFNk and the like.
  • the term "viral vector” refers to any suitable viral vector for delivery of a protein of interest (eg, an interferon) into a target cell or tissue, including but not limited to, for example, an adenoviral vector, an adeno-associated viral vector. , retroviral vector, mouse Harvey sarcoma virus vector, mouse mammary tumor virus vector, Rous sarcoma virus vector, SV40-type virus vector, polyoma virus vector, EB virus vector, papilloma virus vector, herpes virus Vector, vaccinia virus vector, sputum scutellaria virus vector and RNA viral vector; preferably, the disease
  • the virulence vector is an adenoviral vector.
  • tumor-associated antigen includes, for example, tumor surface antigens, including but not limited to members such as the epidermal growth factor receptor family (EGFR), including EGFR, HER1, HER2, HER4 and HER8, etc. (Nam, NH , & Parang, ⁇ ⁇ (2003), Current targets for anti cancer drug discovery. Current Drug Targets, 4 (2) , 159-179) , STEAP (six-transmembrane epithelial antigen of the prostate; Hubert et al, STEAP : a prostate-specific cel l-surface ant igen highly expressed in human prostate tumors. , Proc Natl Acad Sci US A. 1999; 96 (25) : 14523-8.
  • EGFR epidermal growth factor receptor family
  • rituximab a chimeric anti-CD20 antibody
  • Campath-1H anti-CD52 antibody
  • antibodies to any cancer-specific cell surface antigen include alemtuzumab (CampathTM) for chronic leukemia; bevacizumab (AvastinTM) For colon and lung cancer; cetuximab (ErbituxTM) for colon and head and neck cancer; jituzumab (MylotargTM) for acute sputum leukemia; Ibritumomab (Zeval inTM) for non-Hodgkin's lymph Tumor; Parumimide (VectibixTM) for colon cancer; RituxanTM non-Hodgkin's lymphoma; Tosimizumab (BexxarTM) for non-Hodgkin's
  • pharmaceutically acceptable carrier means a carrier which does not cause an allergic reaction or other unpleasant effects in the administered cells or subjects, and which does not affect the activity of the drug.
  • Suitable pharmaceutically acceptable carriers include, but are not limited to, for example, one or more of water, physiological saline, phosphate buffer, levulose, glycerol, ethanol, and the like, as well as combinations of the foregoing.
  • the pharmaceutically acceptable carrier may further comprise minor auxiliary substances, such as wetting or emulsifying agents, preservatives or buffers, which increase the shelf life or utility of the nucleic acid, polypeptide, viral particle or cell.
  • defective in interferon and/or its receptor means that the expression of the interferon or interferon receptor does not reach the level required to achieve its biological function, or the interferon expressed Or the interferon receptor is unable to exert the desired biological function (eg, in the form of a mutation), or the interferon (or interferon receptor) is unable to interact with its receptor (ligand) to cause downstream signaling.
  • the following examples are merely illustrative of the invention and are not intended to limit the invention in any way.
  • mice C57BL/6 mice, rats, B6/0TI TCR transgenic mice, Ly5.1 mice and B6/Rag-1 K0 mice were purchased from Jackson Laboratory and were 6-7 weeks old.
  • 2C TCR-transgenic mice were supplied by Jianzhu Chen, MIT, Cambridge, MA and were deposited in the No Specific Pathogen (SPF) facility at the University of Chicago.
  • the B6/IFNA1R K0 mouse was generously provided by Anita Chong of the University of Chicago. For all experiments, mice were 6-16 weeks old, mice were incubated under SPF and mice were used according to animal care and using the Animal Experimental Guide (IACUC) set by the Commission.
  • Cell line C57BL/6 mice, rats, B6/0TI TCR transgenic mice, Ly5.1 mice and B6/Rag-1 K0 mice were purchased from Jackson Laboratory and were 6-7 weeks old.
  • 2C TCR-transgenic mice were supplied by Jianzhu Chen, MIT, Cambridge, MA and were deposited in the No Specific Pathogen (SPF) facility at
  • Bl 6-F10 mouse melanoma cells were obtained from the American Type Culture Collection.
  • B16-SIY melanoma cells and anti-2C TCR (1B2) antibodies were obtained from Tom Gajewski (University of Chicago).
  • the cells were cultured in RPMI 1640 medium containing L-glutamate at 37 ⁇ and 53 ⁇ 4 C0 2 supplemented with 10% FBS, 100 U/ml penicillin, 100 U/ml streptomycin, in the RPMI 1640, lniM sodium pyruvate, 0. ImM non-essential amino acids and HEPES.
  • the B16-SIY cell line was maintained in medium containing G418 (1 mg/ml).
  • RNA purification and gene array analysis B16F1 tumors were irradiated (20 Gy) or not treated. Five hours after irradiation, the tumors were excised, snap frozen in liquid nitrogen and stored at -80 Torr until further processing. The frozen tumors were cut into pieces of about 5 mm 3 in size and soaked overnight in RNA a ICE solution (Applied Biosystems-Ambion). The samples were centrifuged, washed in RLT buffer (QIAGEN), and homogenized on ice using a glass-Teflon homogenizer set to 3000 rpm. Further purification was performed using a combination of RNeasy spin columns and TRIzol reagents as previously described (Khodarev et al., 2004).
  • RNA samples were normalized to a concentration of 1 mg/ml, samples from at least three tumors/group were pooled in equal amounts, and the pooled samples were transferred to a functional genomics facility at the University of Chicago. For labeling and hybridization with the mouse genome 4 30 2. 0 GeneChips® array (Af fymetrix). Selection and analysis of genes differentially expressed in irradiated vs. untreated tumors is based on the process detailed above. (Khodarev et al., 2004; Kimchi et al., 2005; Pitroda et al., 2009).
  • each array was hybridized to pooled total RNA samples.
  • the "integral median normalization" (Kimchi et al., 2005) was used to re-adjust the data throughout the data set and filter the data as described (Khodarev et al., 2004).
  • Subsequent analysis was based on a pairwise comparison of replicate arrays using a saliency analysis of the microarray (Tusher et al., 2001) version 3. 02, setting the false discovery rate to ⁇ 1%.
  • mice Lethal radiation was administered to wild-type (WT) or IFNAR K0 mice with a single dose of 1000 rad.
  • WT wild-type
  • IFNAR K0 mice IFNAR K0 mice
  • 2 - 3 x 106 bone marrow (BM) cells were intravenously transferred to irradiated mice. After reconstitution, the mice were maintained on antibiotics diluted with sulfamethoxazole and trimethoprim (complex sulfamethoxazole) in drinking water for 4 weeks. Tumor cells were injected into mice 5-6 weeks after reconstitution. Subsequent transfer of T cells
  • Lymph node (LN) cells and spleen cells were isolated from 2C or OTI Tg mice. Then, a total of 2 X 10 6 2C or 0T1 T cells labeled with carboxyfluorescein amber Bt imidate (CFSE) were intravenously transferred to C57BL/6 mice bearing B16-SIY tumors. Cells were isolated from draining lymph nodes (DLN), spleen or tumor at the indicated time points. CFSE dilution was evaluated as previously described (Yu et al, 2004; Yu et al, 2007).
  • splenocytes and lymph node cells were collected from ⁇ mice, and Pan T cell isolation kit and automated magnetic cells ⁇ (autoMACSTM Miltenyi Biotec) were used to control T cells.
  • Flow cytometry analysis For reconstitution of RAG K0 recipients, splenocytes and lymph node cells were collected from ⁇ mice, and Pan T cell isolation kit and automated magnetic cells ⁇ (autoMACSTM Miltenyi Biotec) were used to control T cells. Flow cytometry analysis
  • Tumors, DLN and spleen (SP) were excised from the mice, minced and digested with 1.5 mg/ml collagenase, lU/mL dispase and 0.4 mg/ffll DNase I for 40 min at 37 , then added EDTA was brought to a final concentration of 6 mM to inactivate the enzyme.
  • the single cell suspension of the cells was incubated with anti-CD16/32 (anti-FCTI II/II receptor, clone 2. 4G2) for 20 min at room temperature, followed by staining with the following conjugated antibody: anti-CD45. 2 ( Clone 104), anti-CD90. 1 (anti-Thy- 1.
  • the cultured cancer cells were trypsinized, washed with a medium, and subcutaneously injected into the corresponding mice on the back. Tumor size was determined at 3-3-4 day intervals. Tumor volume was measured along three orthogonal axes (a, 6 and c) and the tumor volume was calculated to be equal to a ⁇ /2. Tumor nodules were inoculated in vivo with the indicated amounts of Ad-IFN-P or Ad-null virus tumors. Through and Biogen pou collaborated to obtain Ad-IFN- ⁇ . For antibody-mediated cell depletion, 200/mouse of anti-CD4 or anti-CD8 was administered intraperitoneally to mice on day 9, day 11 and day 13 after inoculation of the original tumor (YTS. 169. 4.
  • mice were subjected to local X-ray radiation at the doses indicated in each experiment using a GE Maxitron x-ray generator. Each mouse was protected with a lead cap to expose the tumor, allowing for local IR (ionizing radiation) radiation.
  • Real-time PCR Real-time PCR
  • Tumors were collected at the indicated time points after topical RT at 20 Gy.
  • Real-time PCR was performed using cDNA prepared from DNase I-treated RNA, which was extracted from the entire tumor or was sorted by the BD FACSAria cell sorter into CD45. 2 CD and CD45. 2_ populations. Single cell suspension extracted.
  • the primers and probes used are as follows. For IFN ⁇ : forward 5' - ATG AGT GGT GGT TGC AGG C-3' (SEQ ID NO: 1), reverse 5' - TGA CCT TTC AAA TGC AGT AGA TTC ⁇ -3' (SEQ ID NO: 2 ).
  • the tumors were collected and weighed at the indicated time points, and were performed on water in IX phosphate buffer (PBS) and IX Hal t protein preparation mixture (Thermo Fisher Scientific). Qualitative. Supernatants were collected and IFN-[beta] was measured using a VeriKine mouse IFN-P ELISA kit (PBL IFN Source) according to the manufacturer's instructions. In vivo specific lysis assay
  • mice were injected subcutaneously with 0.5 ⁇ x0 6 B16-SIY cells. Mice were treated with axltT ad-IFN-P or ad-nul 1 tumors on day 12 and day 14 after injection.
  • An equal number of CFSE-labeled splenocytes were intravenously transferred to mice supplemented with SIY peptide (lyg/ml) or 0T-1 peptide (3). Lyg/ml).
  • Cells supplemented with SIY were labeled with CFSE* ( ⁇ ), while cells filled with 0 ⁇ -1 were labeled with CFSE (1. ⁇ ).
  • Splenocytes loaded with the peptide were also transferred to naive, non-tumor-bearing mice as controls. After 18-24 hours, the spleens of recipient mice were collected and analyzed by FACS. The specific lysis was calculated as follows:
  • % specific lysis [ (%CFSE low X A - %CFSE high) / (%CFSE low x A) ] x 100
  • A % CFSE * (specific peptide - SI Y) divided by % CFSE low (non-specific peptide - 0T-1) (in naive control mice, the results for multiple controls were averaged).
  • mice 5 ⁇ 10 5 B16-SIY tumor cells were subcutaneously injected into the lower back of C57BL/6 mice. After the tumor was established, the mice received local RT (20 Gy) at the tumor and tumors were collected for DC purification after 3 days. The tumor was finely shredded with scissors and a solution containing 1.5 mg/mL j ⁇ , drunk (Sigma), lU/mL drunk (BD Biosciences) and 0.4 mg/mL DNase I (Sigma) was used at 37°. C, digest for 40 minutes in a rotary incubator set to low speed.
  • Live cells from the resulting single cell suspension were subjected to Ficoll-Paque Plus (GE Healthcare) centrifugation, and the isolated cells were used for DC purification using CDllc+ magnetic bead kit and automated magnetic cell sorting (autoMACS) TM Mi lteayi Biotec).
  • autoMACS automated magnetic cell sorting
  • 1x10 5 naive 2C cells were plated with lxlO 5 DCs with or without exogenous SIY peptide (g/ml), and supernatants were collected 3 days later for cell flow according to the manufacturer's instructions.
  • Bead array (CBA) (BD Biosciences) for analysis.
  • the mouse IFN beta cDNA was amplified by PCR and cloned into the Notl/EcoRV site of pAdenoVator-CMV5 (CuO) under the control of the CMV5 promoter.
  • the pAdenoVator-mIFN P was linearized and electroporated into the electrocompetent cell BJ5183 at 2. 5 kV for recombination with the backbone vector containing the adenoviral genome. Selection of hybrids on kanamycin LB agar plates Cosmid. Pad digestion was used to further identify recombinant cosmids containing the insert mlFN P.
  • Ad-mIFN ⁇ DNA was linearized by Pa digestion and the Pa-digested mixture was transfected into 293 cells for further purification without further purification. Recombinant adenovirus.
  • Adenovirus-mIFN P is called Ad- IFN ⁇ .
  • Example 1 Radiation therapy increases intratumoral IFN-P production Since DC maturation is not measurably affected by local RT and individual tumor antigen cross-presentation does not explain increased functionality in DCs from tumors receiving local RT, the inventors propose Local RT may enhance the local tumor microenvironment to respond to DC function through changes in the local cytokine environment. Looking at the obtained gene array data for significant differences in cytokine gene expression, few interesting candidates (data representations) that met the detection threshold were obtained.
  • telomeres RNA-binding protein
  • Fig. la RNA-binding protein
  • Fig. lb protein levels
  • Fig. lc type I IFN was mainly produced by CD45+ hematopoietic cells infiltrating tumors.
  • the inventors tested whether radiation can be directly induced from B16 in vitro. IFN- ⁇ of tumor cells.
  • Example 1 IFN- ⁇ / ⁇ response is critical for the therapeutic effect of RT in order to first test whether type I IFN is critical for RT-mediated tumor reduction, Applicants in wild-type (WT) and IFN receptors
  • WT wild-type
  • IFNaRl K0 alpha knockout mice
  • IFNaRl K0 alpha knockout mice
  • Tumor-bearing mice (15 Gy ⁇ 3) were treated daily with 15 Gy (local) RT and tumor growth was monitored for three consecutive days.
  • Type I IFN exerts a pleiotropic effect including, for example, antiviral, antiproliferative, immunomodulatory and antiangiogenic responses.
  • Common heterozygous dimeric IFN-[alpha]/[beta] receptors are ubiquitously expressed, but the effects of IFN receptor action may vary depending on cell type (Uddin and Platanias, 2004; van Boxel-Dezaire et al, 2006).
  • Due to the IFN-[alpha]/[beta] receptor Puda tumor cells are potential targets for type I IFN, where direct signaling on tumor cells can mediate anti-proliferative effects (Figure 2).
  • the lack of response to RT in the IFNaRI KO host may be due to receptor defects in non-hematopoietic tumor-associated mesenchymal cells, immune cells, or a combination thereof.
  • BM bone marrow
  • the 1000 rad (ie lethal dose) pair or IFNaRl K0 host was irradiated and reconstituted with FT or IFNaRl K0 osteophytes.
  • Treated with a partial burning candle RT (15 Gy x3) Tumor-bearing mice, as expected, tumors gradually grew in both untreated groups
  • IFNaR1 K0 mice responded to RT once the hematopoietic cells were restored to IFN- ⁇ / ⁇ (Fig. 2c). Therefore, in non-tumor cells, an IFN- ⁇ / ⁇ response in the hematopoietic system is required to achieve the therapeutic effect of RT.
  • mice knocked out with the recombinase activating gene were reconstituted with total T cells purified from WT or IFNaR10 mice, and these T cell chimeric mice were inoculated with tumor cells one week after T cell transfer. At the time of inoculation, steady-state expansion of the transferred T cells had stopped (data not shown). Tumors established in T cell chimeric mice were treated with local ablation RT and tumor growth was monitored. As expected, treated mice that received sputum cells were able to control tumor growth (Fig. 2e).
  • RAG recombinase activating gene
  • mice that received IFNaRl KO T cells were still able to mediate equal tumor control after local RT. Therefore, direct T cell responses to type I IFN are not required to achieve RT-mediated tumor control.
  • Example 3 Local RT restored the ability of tumor infiltrating DCs to elicit T cells in an IFN-dependent manner.
  • IFNa R1 K0 DC purified from irradiated tumors does not stimulate the ability of T cells to proliferate, which cannot be restored by the addition of exogenous SIY peptides, and is co-cultured in vitro with the provision of exogenous SIY peptides.
  • Stimulation of TLR with bacterial lipopolysaccharide (LPS) peptides failed to restore the ability of TIDCs to stimulate T cell proliferation (Fig. 3a), and these results further confirmed the results previously obtained by the inventors in wild type mice.
  • IFNa Rl KO DC maturation of IFNa Rl KO DC was assessed by surface staining with MHC class I, MHC class II, B7-1, B7-2 and CCR7, showing expression equivalent to FT TIDC, which was obtained from treated and not No significant differences were observed between DCs of treated tumors (data not shown). Furthermore, because TNFa production in response to LPS is equivalent (if not increased) compared to WT TIDCs from irradiated tumors, IFNa Rl KO TIDC is unlikely to be fully functionally compromised (Fig. 3c). In order to confirm that the function of DC was not completely impaired in IFNa Rl KO mice, the inventors analyzed DCs isolated from tumor-draining lymph nodes of IFNa Rl KO mice.
  • lymph node DCs between WT and IFNa Rl KO mice were functionally indistinguishable (Fig. 3d and data not shown).
  • DCs from the lymph nodes of WT and IFNa Rl KO mice also showed an equivalent response to LPS as measured by TNFa production (data not shown). Therefore, RT-directed type I IFN is required for obtaining DC cross-inducing ability in the microenvironment of tumors.
  • Example 4 The tumor reduction caused by local delivery of type I IFN to the source is dependent on CD8+
  • type I IFN is a key downstream mediator of local RT, however, local RT has the potential to induce many factors that affect tumor control and rejection.
  • ad-IFNp recombinant adenoviral vector
  • the inventors tested Whether local delivery of type I IFN to a tumor by recombinant adenoviral vector (ad-IFNp) can cause tumor rejection.
  • the inventors treated established B16-SIY tumors with ad-null (blank vector control) or ad-IFN-P and monitored tumor growth. Surprisingly, even for this aggressive tumor, ad-IFN-p also showed a very strong anti-tumor effect (Fig. 4a).
  • ad-IFN- ⁇ may have multiple inhibitory effects on B16-SIY tumor cells, in order to test for the inhibition of sputum cells, the inventors used B6/RAG K0 mice (these mice are defective in lymphocytes). And compared to untransferred hosts and those reconstituted with sputum cells collected from wild-type donors. Interestingly, a tumor response to ad-IFN- ⁇ was not detected in Rag-1+ mice, but it was restored by transferring peripheral sputum cells (Fig. 4b). Therefore, the treatment with ad-IFN-P is immune-mediated and dependent on T cells, as is the case with RT treatment.
  • CD8 + T cells are critical for the anti-tumor effect of ad-IFN- ⁇ .
  • Example 5 IFN- ⁇ causes preferred amplification of antigen-specific sputum cells. Since the inventors determined that the therapeutic effect of ad-IFN- ⁇ depends on CD8 + T cells (Fig. 4b, c), the inventors hypothesized that it is like radiation therapy. , ad-IFN- ⁇ can induce antigen-specific T cell initiation and expansion. To test this, the inventors transferred naive 2C transgenic T cells recognizing the SIY antigen into mice bearing B16-SIY tumors.
  • ad-IFN-P After treatment with ad-IFN-P, the inventors collected draining lymph nodes (DLN) and used clonal antibody 1B2 (anti-2C TCR) to quantify antigen-specific CD8+ T cell expansion. Treatment with ad- resulted in an approximately 6-fold increase in antigen-specific cells compared to ad-null (data not shown). This significant increase is likely due to antigen-driven proliferation, however, the following possibilities exist: ad-IFN- Beta can generally promote non-specific amplification of cells by reversing the inhibitory cytokine environment or by creating space by IFN-[alpha]/[beta]-mediated apoptosis of sputum cells.
  • Type I IFN has also been shown to be involved in mediating bystander cell proliferation (Tough et al., 1996). Type I IFN is critical for viral infection and has been shown to be decisive for infection by some bacteria (eg, Listeria monocytogenes) (Auerbuch et al., 2004; Carrero et al., 2004; O' Connel l et al., 2004). Therefore, it is still unclear what effect IFNP released from tumor tissue after treatment will have on antigen-specific T cell immune responses.
  • 2C and 0T-1 (non-specific) cells were then transferred to mice bearing B16-SIY tumors.
  • CFSE carboxyfluorescein succinimidyl ester
  • the inventors utilized 0T-1 cells containing a congenic marker (Thyl. 1). Five days after treatment with ad-nul l or ad-IFN-P, the degree of CFSE dilution of 1B2+CD8+ (antigen-specific cells) in DLN and spleen relative to Thyl.l + CD8 + (non-specific) was determined.
  • Ad-IFN-P induced a preferred amplification of antigen-specific 2C cells compared to non-specific OT-1 cells (Fig. 5a-c).
  • the ratio of 2C to OT-1 TCR transgenic cells was approximately equal, confirming that a similar number of transgenic Ts were transferred to the recipient, but the therapeutic effect of ad-IFN-P was Significantly increased (Figure 5c).
  • 2C cells showed vigorous proliferation, which was confirmed by almost complete CFSE dilution (Fig. 5d). In contrast, non-specific cells were unable to proliferate (data not shown).
  • Example 6 Increased antigen-specific cytolytic activity in vivo Although proliferation is a good indicator of an effective immune response, it does not always translate into potent effector functions. Therefore, the inventors investigated whether ad-therapy causes increased in vivo specific lysis. Tumor-bearing mice were treated with ad- nul l or ad-IFN-P, and then target cells loaded with CFSE-labeled peptides were transferred thereto.
  • TUB0-EGFR cells were inoculated and IFN-expressing adenoviruses were injected intratumorly on day 14, 17 and 20 days.
  • Ad- nul l has a mild effect on tumor growth, while ad- causes tumor regression ( Figure 6). This suggests that local delivery of ad-IFN beta on TUB0 can also induce a strong response, causing tumor regression.
  • HC-Fc-IFN is cloned into the vector Abvec-hlgGl; 2) the light chain of the antibody is cloned into the vector Abvec-lamda;
  • the HC-Fc-IFN is cleaved from the product obtained in 1) and cloned into the lonza vector pEE6.4 by blunt-end ligation;
  • the light chain is cleaved from the product obtained in step 2) And cloning it into lonza vector PEE12.4 by blunt-end ligation; 5) excising the expression cassette from the product of step 4) and cloning it into the product of step 3), thereby obtaining the final plasmid pEEl 2 4 - anti-EGFR-IFNP) plasmid was transfected into CH0 cells and cells expressing the fusion protein were selected in large amounts.
  • the supernatant of CH0 containing this plasmid was collected and the fusion protein was purified by Protein A column, the protein A The column binds the Fc portion of the fusion protein with high affinity.
  • the antibody or the antibody-IFN was used to treat mice bearing TUB0-EGFR. Only the fusion protein caused tumor tachycardia regression (Fig. 7). Similar results were obtained from mice bearing B16-EGFR tumors ( Figure 8) Thus, this fusion protein can also be used to better eliminate tumors that express EGFR in tumors compared to antibodies alone.
  • mice bearing EGFR-TUB0 tumors were treated with low doses of the fusion protein and T cell depleting antibodies. Although the growth of EGFR-TUB0 was significantly delayed, depletion of CD8+ T cells caused rapid recurrence, whereas depletion of CD4+ T cells did not cause tumors (JL) (Fig. 9).
  • HMG-1 High mobility group 1 protein
  • HMGB1 High-mobility group box 1
  • Type I IFNs provide a third signal to CD8 T cells to stimulate clonal expansion and differentiation. J Immunol 174 , 4465-4469.
  • Type I interferon is selectively required by dendritic cel ls for immune rejection of tumors. The Journal of exper imental medicine 208, 1989-2003.
  • Khodarev, NN Beckett, M., Labay, E., Darga, T., Roizman, B., and Weichselbaum, RR (2004) .
  • STATl is overexpressed in tumors selected for radioresitance and confers protect ion from radiation in transduced sensi tive Cel ls. Proc Natl Acad Sci USA 101, 1714-1719.
  • STATl Pathway mediates ampl if ication of metastatic potential and resistance to therapy.
  • Type I interferons act directly on CD8 T cel ls to al low clonal expansion and memory formation in response to Viral infection.

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Abstract

La présente invention concerne l'utilisation d'un interféron (IFN) dans le traitement/la prévention de tumeurs résistantes à la thérapie anti-tumorale classique, telle que la radiothérapie et la chimiothérapie, et/ou concerne l'utilisation dudit interféron en combinaison avec d'autres thérapies anti-tumorales, et concerne une composition et trousse associées.
PCT/CN2013/077453 2012-06-19 2013-06-19 Utilisation d'interféron dans le traitement/la prévention de tumeurs résistantes à la thérapie anti-tumorale classique WO2013189287A1 (fr)

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BURNETTE, B.C. ET AL.: "The Efficacy of Radiotherapy Relies upon Induction of Type I Interferon-Dependent Innate and Adaptive Immunity", CANCER RESEARCH, vol. 71, no. 9, 1 April 2011 (2011-04-01), pages 2488 - 2496 *

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