70 results about "Antitumor immunity" patented technology

The present invention is based on the seminal discovery that targeted immunomodulatory antobodies and fusion proteins can counter act or reverse immune tolerance of cancer cells. Cancer cells are able to escape elimination by chemotherapeutic agents or tumor-targeted antobodies via specific immunosuppressive mechanisms in the tumor microenvironment and such ability of cancer cells is recognized as immune tolerance. Such immuno-suppressive mechanisms include immunosuppressive cytokines (for example, Transforming growth factor beta (TGF-β)) and regulatory T cells and / or immunosuppressive myeloid dendritic cells (DCs). By conteracting tumor-induced immune tolerance, the present invention provides effective compositions and methods for cancer treatment, optional in combination with another existing cancer treatment. The present invention provides strategies to counteract tumor-induced immune tolerance and enhance the antitumor efficacy of chemotherapy by activating and leveraging T cell-mediated adaptive antitumor immunity against resistant or disseminated cancer cells.

The present invention is based on the seminal discovery that targeted immunomodulatory antibodies and fusion proteins can counter act or reverse immune tolerance of cancer cells. Cancer cells are able to escape elimination by chemotherapeutic agents or tumor-targeted antibodies via specific immunosuppressive mechanisms in the tumor microenvironment and such ability of cancer cells is recognized as immune tolerance. Such immune suppressive mechanisms include immunosuppressive cytokines (for example, Transforming growth factor beta (TGF-β) and regulatory T cells and / or immunosuppressive myeloid dendritic cells (DCs). By counteracting tumor-induced immune tolerance, the present invention provides effective compositions and methods for cancer treatment, optional in combination with another existing cancer treatment. The present invention provides strategies to counteract tumor-induced immune tolerance and enhance the antitumor efficacy of chemotherapy by activating and leveraging T cell-mediated adaptive antitumor immunity against resistant or disseminated cancer cells.

Efficacy of a therapeutic to enhance antitumor immunity in a patient is predicted, where the therapeutic is one that targets an immunomodulatory leukocyte membrane protein (ILMP) to enhance immune activity. Peripheral blood sample from the patient is tested for levels of monocytes having specific cell surface markers (CD14+, HLA-DRlow) prior to treatment. Low levels of monocytes of this type (PBM14+HLA-DRlow) indicate a greater likelihood of therapeutic efficacy. In specific exemplary embodiments of the invention, the therapeutic is an antibody to CTLA4, such as ipilimumab or tremelimumab.

The present invention is intended to provide a pharmaceutical composition for delivering a chemotherapeutic, preferably an anticancer drug, into cells or into a living organism, using a viral envelope vector, and provides a pharmaceutical composition comprising a chemotherapeutic encapsulated in, or used in combination with, a viral envelope vector having an adjuvanticity as an active ingredient. Thereby it is possible to introduce an anticancer drug encapsulated in a viral envelope vector directly into a tumor, with coadministration of another anticancer drug so as to induce tumor cell-specific antitumor immunity also thanks to the adjuvant action of HVJ-E, and hence to regress the tumor. The present invention also provides a pharmaceutical composition comprising a viral envelope vector and a chemotherapeutic as active ingredients.

Nanoconstructs having three components: (1) biodegradable nanopolymers and nanoparticles, (2) immunodrugs such as CpG, and a (3) tumor binding device, which are actively targeted to tumor cells such as melanoma cells through receptor-mediated uptake and methods of using the same are described. Antitumor immunity is further enhanced by combination of PG-CpG nanoconstructs with agonists of positive costimulatory signals and inhibitors of negative immune regulatory signals.

Disclosed is a method of treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound that inhibits a plurality of mammalian dipeptidyl peptidase (DPP) IV activity and / or structural homologues thereof (DASH) serine proteases. Also disclosed is a method of (a) increasing antitumor immunity, (b) stimulating or enhancing an immune response, (c) treating a condition characterized by abnormal cell proliferation, (d) increasing cytokine and / or chemokine production, or (e) stimulating or enhancing production of T-cells, in a mammal, comprising administering to a mammal in need thereof an effective amount of a compound that inhibits a plurality of mammalian DASH serine proteases. For example, the compound that inhibits a plurality of mammalian DASH serine proteases may be t-butylGly-boroPro.

Nanoconstructs having three components: (1) biodegradable nanopolymers and nanoparticles, (2) immunodrugs such as CpG, and a (3) tumor binding device, which are actively targeted to tumor cells such as melanoma cells through receptor-mediated uptake and methods of using the same are described. Antitumor immunity is further enhanced by combination of PG-CpG nanoconstructs with agonists of positive costimulatory signals and inhibitors of negative immune regulatory signals.

The present invention relates to modulation of the tumor microenvironment to increase cancer specific immune responses. Conjugates, nanoparticles and formulations of the present invention relieve the inhibitory effect induced by tumor cells, and enhance antitumor immunity. The compostions provided herein can be used as immunotherapies, or as adjuvants used in conjunction with other immunotherapies such as peptide vaccines, cell vaccines and / or adoptive T cell transfer.

The present invention is intended to provide a pharmaceutical composition for delivering a chemotherapeutic, preferably an anticancer drug, into cells or into a living organism, using a viral envelope vector, and provides a pharmaceutical composition comprising a chemotherapeutic encapsulated in, or used in combination with, a viral envelope vector having an adjuvanticity as an active ingredient. Thereby it is possible to introduce an anticancer drug encapsulated in a viral envelope vector directly into a tumor, with coadministration of another anticancer drug so as to induce tumor cell-specific antitumor immunity also thanks to the adjuvant action of HVJ-E, and hence to regress the tumor. The present invention also provides a pharmaceutical composition comprising a viral envelope vector and a chemotherapeutic as active ingredients.

Provided are polynucleotides and viral vectors, particularly, alphavirus vectors such as Sindbis viral vectors, which encode multiple, e.g., two or more, epitopes of at least one tumor associated antigen in which each epitope is separated by a processing or enzyme cleavage site. The multiple epitopes of the two or more tumor associated antigens encoded by the described polynucleotides and viral vectors may be the same or different. Methods of treating mammalian subjects having a cancer or tumor expressing the tumor associated antigen epitopes are provided, in which the viral vectors encoding the multiple epitopes, as well as other immunostimulatory or immunomodulatory components, generate an anti-cancer or anti-tumor immune response in which high levels of effector T cells increase the survivability of tumored mammalian subjects and result in epitope spreading, thus providing a further enhancement of the immune response.

The present invention is directed to the administration of FusOn-H2, an HSV derived oncolytic virus, to treat tumor cells that are resistant to the lytic effect of the virus. Administration of FusOn-H2 induces the patient's innate immune responses to tumor cells via neutrophils, which are able to destroy tumors efficiently when they migrate to the tumor mass. With the induced innate antitumor immunity, FusOn-H2 is effective at eradicating tumors even when it is used at very low doses.

The invention discloses a preparation method and applications of hollow gold nanospheres modified by CpG oligodeoxynucleotide. Cobalt chloride is subjected to reduction by adopting sodium borohydride,thus cobalt nanoparticles are obtained, cobalt nanoparticles are adopted for carrying out reduction on chloroauric acid, and thus hollow gold nanospheres are prepared; CpG oligodeoxynucleotide, a surfactant and a buffer solution are added into a solution of the hollow gold nanospheres, shaking culture is carried out, and thus the hollow gold nanosphere material modified by CpG oligodeoxynucleotide is obtained. According to the technical scheme, by utilizing the property that the hollow gold nanospheres have the large loading capacity, CpG is loaded through the self-assembly effect, the synthesis method is simple, and the method is suitable for large-scale production and application; the cell uptake capacity of CpG oligodeoxynucleotide can be enhanced, and the biocompatibility is good; thehollow gold nanospheres modified by CpG oligodeoxynucleotide have the near-infrared surface plasma adsorbing effect, the primary tumor is eliminated by utilizing the photothermal ablation effect, a tumor antigen is generated in situ, under the promoting of CpG oligodeoxynucleotide, the antitumor immunity of the whole body is induced, and the distant metastasis tumor is further treated.

The invention provides a method for preventing tumor-induced T cell aging and reversing immunosuppression capability of the tumor-induced T cell. A ligand of a TOLL like receptor 8 is provided to a cell; a TOLL like receptor 8 (TLR8) signal channel in a tumor cell is activated; the tumor-induced T cell aging is blocked up, so as to improve the antitumor immunity. The ligand of the TOLL like receptor 8 is characterized by being oligonucleotides and comprising adenine, guanine, a main chain connecting bond for connecting the guanine and nuclease resistance residue of adjacent nucleic acid bases (preferably a chemical bond is phosphorothioate); a nucleic acid synthesis sequence is 5'-AGG...GA-3'; G represents guanine; A represents adenine; G and G are modified by a dithio phosphate ester bond; the number of G may be 3 to10 in difference; an acid synthesis sequence of a common ligand Poly-G3 is 5'-AGGGA-3'. By injecting TLR8 ligand Poly-G3 into the tumor, the inhibitory effect of a CD8<+>T cell can be significantly enhanced.

CD4<+> regulatory T (Treg) cells profoundly suppress host immune responses and thus protect against autoimmune disease while restricting desired immune responses such as antitumor immunity. Synthetic phosphorothioate-protected, guanosine-containing oligonucleotides can directly reverse the suppressive activity of Treg cells without involving dendritic cells. This effect appears to be transduced by signaling through Toll-like receptor (TLR) 8 and engagement of the MyD88 and IRAK4 molecules in Treg cells. Stimulation of Treg cells with natural ligands for human TLR8 recapitulated the effect of the synthetic guanosine-containing oligonucleotides .

The present invention discloses in-situ transplantation process of constructing human liver cancer mouse model. The process includes using Kunming sucking mouse as the tumor carrying acceptor, and injecting the mouse liver lobes with human liver cancer cell suspension to in-situ transplanted tumor carrying model of human liver cancer cell. The process is simple and high in successful rate. The process makes it possible to monitor the mutual effect between liver cancer cell and mouse immune system under normal mouse body immune environment, simulate the whole process of immunological tolerance and antitumor immunity in human body and provide ideal operation platform for the immunobiological medicine screening and pharmacological research.

The invention provides a gamma delta-T cell exosome used for tumor immunotherapy. The gamma delta-T cell exosome is loaded with miR-138. The exosome (gamma delta TDE) derived from gamma delta-T cellscarries exogenous miR-138 for realizing direct targeted recognition and killing on tumor cells, meanwhile, PD-1 / PD-L1 is inhibited, the antitumor immunity activity of T lymphocytes / NK cells is enhanced, and the effect of inhibiting tumor growth / invasion / metastasis is achieved through direct and indirect paths.

The present invention discloses method of inducing antitumor immunity and its application in preparing medicine. The method is to induce antitumor immunity with live myeloma FO cell, freeze dried powder of GM-CSF transfected myeloma FO cell, primary human umbilical vein vessel endothelial cell, or the extract of tumor vessel endothelial cell membrane surface protein. The method may be used in preparing antitumor medicine and has simple operation and high antitumor immunity inducing effect.

The invention relates to antitumor application of chlorambucil-polydopamine prodrug nanoparticles, and concretely relates to a mild photothermal therapy-chemotherapy combined tumor alete treatment technology based on the chlorambucil-polydopamine prodrug nanoparticles. The nanoparticles can realize spatiotemporal manipulation in an antitumor effect in order to achieve accurately-positioned tumor ablation, and passive targeting action of the prodrug nanoparticles on tumor parts can be achieved by the enhanced permeation and retention(EPR) effect; the mild photothermal effect can enhance the expansion of tumor blood vessels and the permeability of cell membrane effectively promote the accumulation and penetration of the nanoparticles in tumors and the endocytosis of tumor cells; and photothermal therapy can induce the antitumor immunity in order to improve the effect of chemotherapy, so synergistic antitumor effects are generated in the photothermotherapy-chemotherapy combined therapy. The application provides a new way for precise cancer treatment, and has a potential clinical application prospect.

The invention relates to application of inactivated plasmodium to preparing medicine for treating cancer. According to the application, a high-purity inactivated-plasmodium antigen mixture is obtainedthrough density gradient centrifugation and ultrasonication, and serves as an antigen for adjusting activities of host dendritic cells and natural killer cells, a series of immunologic effector cellssuch as T cells and B cells are activated, a systematic immune response of host is comprehensively activated, an antitumor immunity response of a main body can be enhanced, and the inactivated plasmodium has the potential antitumor activity, and provides new strategy and thinking for cancer of treatment.

The invention discloses application of bacillus coagulans to preparing antitumor immunity inducing and immune checkpoint inhibitor sensitizing agents. Specifically, the bacillus coagulans is applied as a major active component to preparing biological agents such as drugs and combining with immune checkpoint inhibitor to treat cancers. The prepared antitumor immunity inducing and immune checkpointinhibitor sensitizing agents can effectively induce antitumor immunity, enhance the response and treatment effects of the immune checkpoint inhibitor, reduce side effects and prolong the survival period.

The invention discloses application of clostridium butyricum in preparing a preparation for inducing antitumor immunity and enhancing sensitivity of an immune checkpoint inhibitor. Specifically, the clostridium butyricum serves as a main active ingredient to be prepared into a drug and other biological preparations, and the drug or other biological preparations are combined with the immune checkpoint inhibitor for treating cancers. By means of the preparation, the antitumor immunity can be effectively induced, the response rate and treatment effect of the immune checkpoint inhibitor are improved, the side effects are lowered, and the lifetime is prolonged.

The invention provides preparation of broad spectrum antitumor mouse mold with apoptotic body vaccine immunity, wherein the mouse is prepared through the apoptotic body vaccine immunity and has the broad spectrum antitumor property. An establishment method includes: 1) in vitro, inducing apoptosis of cancer cells through a nutrient deficiency process to acquire the apoptotic body; 2) immunizing aKunming mouse with the apoptotic body by subcutaneous injection of 25 mg / kg of the apoptotic body to every mouse once per week, the injection lasting for five weeks in total. In vivo antitumor experimental results of the mouse prove that the anti-tumor rate on H22 tumor-bearing mice can reach 80.27% and model forming successful rate can reach 50%. The invention directs at problems that in a present experiment of immunizing antitumor animals, a positive control model is not reasonable and there is no broad spectrum immuno-antitumor mouse on market, whereas the mouse immunized by the apoptotic body solves the problem. The product has stronger antitumor immunity, is stable in model and is high in production quality.

CD4+ regulatory T (Treg) cells profoundly suppress host immune responses and thus protect against autoimmune disease while restricting desired immune responses such as antitumor immunity. Synthetic phosphorothioate-protected, guanosine-containing oligonucleotides can directly reverse the suppressive activity of Treg cells without involving dendritic cells. This effect appears to be transduced by signaling through Toll-like receptor (TLR) 8 and engagement of the MyD88 and IRAK4 molecules in Treg cells. Stimulation of Treg cells with natural ligands for human TLR8 recapitulated the effect of the synthetic guanosine-containing oligonucleotides .

Adjuvant combinations comprising at least one NKT activator, such as alpha-galactosylceramide (α-Gal-Cer) or iGb3, a CD40 agonist and optionally an antigen are disclosed. The use of these immune adjuvants for treatment of various chronic diseases such as cancers is also provided.

Disclosed is a method of treating cancer, comprising administering to a mammal in need thereof a therapeutically effective amount of a compound that inhibits a plurality of mammalian dipeptidyl peptidase (DPP) IV activity and / or structural homologues thereof (DASH) serine proteases. Also disclosed is a method of (a) increasing antitumor immunity, (b) stimulating or enhancing an immune response, (c) treating a condition characterized by abnormal cell proliferation, (d) increasing cytokine and / or chemokine production, or (e) stimulating or enhancing production of T-cells, in a mammal, comprising administering to a mammal in need thereof an effective amount of a compound that inhibits a plurality of mammalian DASH serine proteases. For example, the compound that inhibits a plurality of mammalian DASH serine proteases may be t-butylGly-boroPro.

The invention relates to the technical field of cancer treatment by T cell, and particularly relates to a composite containing anti-PD-1 gene and polycation and its application in treating tumor; the composite includes poly-cationic polymer and anti PD-1 gene in the mass ratio of 1-100: 1. The composite is transfected to the T cell externally, and the secretion anti OD-1 antibody-T cell is prepared, and PD-1 antibody can be generated, thus helping to stop the PD-1 signal, effectively helping the exhausted T cell, and promoting the T cell treatment cancer of antitumor immunity response. Compared with the prior art, the secretion anti OD-1 antibody-T cell can effectively treat tumor and realize the tumor immunological therapy; besides, the composite is free from in-vivo toxicity.

The invention belongs to the technical field of novel pharmaceutical preparation, relates to humanization tumor immune cell cytokines and in particular relates to a humanization tumor immune cell cytokines TNTIL2, as well as a preparation method and an application thereof. A humanization recombination antibody technology is utilized to prepare a humanization anti-tumor cell nucleus monoclonal antibody, and the humanization monoclonal antibody and interleukin-2 (IL-2) are in fusion expression so as to prepare a TNTIL2 fusion protein, wherein the IL-2 can specifically reach tumor parts, and can be used for reversing the local immunosuppression state of tumors and activating part bodies and integral antitumor immunity. The prepared TNTIL2 can serve as an anti-tumor candidate pharmaceutical with a treatment effect on various solid tumors. The active peptide immune cell cytokines with an immune regulation function can be used for separate or auxiliary tumor treatment.

The present invention relates to an oncolytic adenovirus simultaneously expressing interleukin-12 and shVEGF, and an antitumor immunity enhancing composition and an anticancer effect promoting composition each containing the same. The present inventors verified that the simultaneous occurrence of VEGF inhibition and IL-12 expression induced the recovery of an immune function and the promotion of an anticancer effect in an immunological mouse melanoma or kidney cancer model. Especially, the applicability of a gene carrier simultaneously expressing IL-2 and shVEGF in the cancer gene therapy was first established by disclosing that the increased anticancer effect is involved in an increase in anticancer immunity, an increase in TH 1 cytokine, and the prevention of tumor induced thymic atrophy.

The invention relates to an application of ursolic acid to antitumor immunity. The ursolic acid has the functions of inhibiting the proliferation and inducing the apoptosis of the hepatoma carcinoma cell of a mouse. The in vivo experiments on the mouse show that the ursolic acid has the function of effectively inhibiting the proliferation of the transplanted hepatocellular carcinoma and has no significant side and toxic effects on the mouse. The ursolic acid has the functions of inhibiting the spleen index which increases abornormally due to hepatic tumor, promoting the proliferation of the T lymphocyte and the B lymphocyte significantly, increasing the proportion of the content of the CD4<+>T lymphocyte subset to that of the content of the CD4<+> / CD8<+T> lymphocyte subset, promoting the expression of IL-2 (interleukin-2) which is a serum cell factor, the TNF-alpha (tumor necrosis factor alpha) and reducing the expression of the IL-4 (interleukin-4). The ursolic acid is similar to the cyclophosphamide which is a low-dose antitumor medicament in the antitumor effect and the immunoregulation function, has low toxicity and can be applied to antitumor immunity to provide a theoretical basis for the development of an antitumor immunity medicament.

The invention provides a method for preventing tumor-induced T cell aging and reversing immunosuppression capability of the tumor-induced T cell. A ligand of a TOLL like receptor 8 is provided to a cell; a TOLL like receptor 8 (TLR8) signal channel in a tumor cell is activated; the tumor-induced T cell aging is blocked up, so as to improve the antitumor immunity. The ligand of the TOLL like receptor 8 is characterized by being oligonucleotides and comprising adenine, guanine, a main chain connecting bond for connecting the guanine and nuclease resistance residue of adjacent nucleic acid bases (preferably a chemical bond is phosphorothioate); a nucleic acid synthesis sequence is 5'-AGG...GA-3'; G represents guanine; A represents adenine; G and G are modified by a dithio phosphate ester bond; the number of G may be 3 to10 in difference; an acid synthesis sequence of a common ligand Poly-G3 is 5'-AGGGA-3'. By injecting TLR8 ligand Poly-G3 into the tumor, the inhibitory effect of a CD8<+>T cell can be significantly enhanced.