51 results about "T-cell depletion" patented technology

Methods and compositions for treating an infection or disease that results from (1) failure to elicit rapid T cell mediated responses, (2) induction of T cell exhaustion, T cell anergy or both, or (3) failure to activate monocytes, macrophages, dendritic cells and / or other APCs, for example, as required to kill intracellular pathogens. The method and compositions solve the problem of undesired T cell inhibition by simultaneously inhibiting the PD-1 ligands, PD-L1 and PD-L2. The immune response can be modulated by providing antagonists which bind with different affinity, by varying the dosage of agent which is administered, by intermittent dosing over a regime, and combinations thereof, that provides for dissociation of agent from the molecule to which it is bound prior to being administered again. In some cases it may be particularly desirable to stimulate the immune system, then remove the stimulation.

Methods and compositions for treating an infection or disease that results from (1) failure to elicit rapid T cell mediated responses, (2) induction of T cell exhaustion, T cell anergy or both, or (3) failure to activate monocytes, macrophages, dendritic cells and / or other APCs, for example, as required to kill intracellular pathogens. The method and compositions solve the problem of undesired T cell inhibition by binding to and blocking PD-1 to prevent or reduce inhibitory signal transduction, or by binding to ligands of PD-1 such as PD-L1, thereby preventing (in whole or in part) the ligand from binding to PD-1 to deliver an inhibitory signal. The immune response can be modulated by providing antagonists which bind with different affinity (i.e., more or less as required), by varying the dosage of agent which is administered, by intermittent dosing over a regime, and combinations thereof, that provides for dissociation of agent from the molecule to which it is bound prior to being administered again (similar to what occurs with antigen elicitation using priming and boosting). In some cases it may be particularly desirable to stimulate the immune system, then remove the stimulation.

A method of treating a subject in need of a non-syngeneic cell or tissue graft is disclosed. The methos comprising: (a) transplanting into a subject a dose of T cell depleted immature hematopoetic cells, wherein the T cell depleted immature hematopoetic cells comprise less than 5×105 CD3+ T cells per kilogram body weight of the subject, and wherein the dose comprises at least about 5×106 CD34+ cells per kilogram body weight of the subject, and wherein the T cell depleted immature hematopoetic cells are obtained by separating the T cells from the immature hematopoetic cells by magnetic cell sorting, and (b) administering to the subject a therapeutically effective amount of cyclophosphamide, wherein the therapeutically effective amount comprises 25-200 mg per body weight, thereby treating the subject.

A method for treating or preventing a Human Immunodeficiency Virus (HIV) infection, or treating or preventing Acquired Human Immunodeficiency Syndrome (AIDS), in a subject in need thereof, is disclosed. The method involves colonizing a genetically modified probiotic Lactobacillus reuteri RC-14 in the gastrointestinal tract of a subject, wherein the probiotic is able to secrete two or more fusion inhibitors that decrease or prevent HIV production and CD4+T cell depletion in the gastrointestinal tract.

Provided herein are methods and compositions useful for the replenishment of blood cells in a mammal after exposure to therapeutic radiation or drugs. Radiation illness can be reduced in animals by treatment with substance P analogs. In one embodiment, granulocytes can be regenerated after therapeutic radiation by the administration of a substance P analog. In one embodiment, substance P analogs are useful for reducing PARP activity or PARP expression. In one embodiment, substance P analogs are useful for preventing, reducing or ameliorating adverse effects of drugs. In one embodiment, drug induced blood dyscrasias can be ameliorated by the methods and compositions provided herein.

Chimeric antibodies specific to human CD4 antigen, DNA encoding, pharmaceutical compositions containing and use thereof as therapeutic agents are taught. These chimeric antibodies contain Old World monkey variable sequences and human constant domain sequences, preferably human gamma 1, gamma 4 or mutated forms thereof. These antibodies possess desirable therapeutic properties including low antigenicity, reduced (or absent) T cell depleting activity, good affinity to human CD4 and enhanced stability (in vivo half-life).

The invention discloses a preparation method of a high-efficiency killer cell preparation adopting an immunodetection point dual-block CTL (cytotoxic lymphocyte). The preparation method comprises steps as follows: step 1), collecting mononuclear cells in peripheral blood; step 2), performing DC (dendritic cell) separation and T cell separation on the separated mononuclear cells with an adherence method; step 3), adding adhering DCs to a serum-free culture medium containing GM-CSF (granulocyte-macrophage colony-stimulating factor) and IL-4 (interleukin-4) for preparation of a DC vaccine; step 4), adding suspending T cells to CD3 and IL-2 for T cell culture and amplification; step 5), adding antigen-supported DCs to the amplified T cells for preparation of the CTL, and adding PD-1 (Programmed death 1) and CTLA-4 (cytotoxic t lymphocyte associated antigen-4) antibodies for preparation of the cell preparation with the dual-block CTL effect. According to the novel technology and the novel method provided by the invention, an immune brake effect is effectively regulated and T cell depletion is retarded by blocking inhibitory molecules on the tumor specific CTL surfaces, so that the tumor cytotoxicity of CTL effector cells is substantially improved.

The application relates to methods of assessing whether an individual has an exhausted CD8+ T cell or lack of CD4+ T cell costimulation phenotype, and the use of such methods in determining an individual's risk of autoimmune disease progression, progression of a chronic infection, not responding to a treatment for a chronic infection, not mounting an effective immune response to vaccination, infection-associated immunopathology, transplant rejection, or cancer progression. The application also relates to in vitro methods for assessing whether CD8+ and CD4+ T cells in a sample have an exhausted CD8+ T cell or lack of CD4+ T cell costimulation phenotype, and for identifying a substance capable of inducing an exhausted CD8+ T cell or lack of CD4+ T cell costimulation phenotype in an individual, as well as a kit for assessing whether an individual has an exhausted CD8+ T cell or lack of CD4+ T cell costimulation phenotype or whether an exhausted CD8+ T cell or lack of CD4+ T cell costimulation phenotype is present in a sample of CD8+ and CD4+ T cells.

The invention discloses an application of RBPJ as a drug target in preparation of a drug for inhibiting T cell depletion. The RBPJ can be used as a drug target for preparing a drug for inhibiting T cell depletion; the invention discloses a T cell depletion inhibitor. The inhibitor is an inhibitor for inhibiting the expression quantity of RBPJ. According to the invention, the RBPJ gene capable of being used as a target for preparing the medicine for inhibiting T cell depletion is obtained through screening, and the inhibitor capable of inhibiting the gene expression is designed and synthesized,so that the T cell depletion is effectively inhibited, and the tumor immunotherapy effect is enhanced.

The invention relates to a method for reducing T cell depletion and a medicine which has the function and can be used for clinical treatment. The medicament specifically comprises an anti-CD39 antibody medicament. According to the therapeutic dose level, the anti-CD39 antibody drug can reduce the expression quantity of CD39 on the surfaces of CD45 positive immune cells. And the CD39 structural domain recognized by the anti-CD39 antibody drug is included in the CD39 structural domain combined with the group of antibodies PB1, PB2, PB3, PB4 and PB5. The anti-CD39 antibody drug can also be effectively combined to Fc gamma RIIIa of cells.

Provided is a gRNA targeting HPK1 and a method for editing HPK1 gene. The method can knock out the T cell HPK1 gene, enhance the T cell killing activity, increase the Th1 cytokine level of peripheralblood mononuclear cells, and knock out of the T cell HPK1 gene can also down-regulate the expression of PD-1 and TIM3 on the T cell surface and can inhibit the T cell depletion.

The invention discloses an SH2D1A gene and application of sgRNA to preparation of medicine for T cell depletion recovery or medicine for resisting to a tumor, and relates to the field of T cell molecular biology. By finding, detecting and applying genes with most remarkable expression difference in CD8+T cells with different depletion degrees, through high-throughput RNA sequencing, SH2D1A has animportant adjusting effect in genesis and development of CD8+T cell depletion, and SH2D1A expression is closely related to the genesis and development of CD8+T cell depletion; then, according to the coding sequence of SH2D1A, sgRNA is designed and synthesized, through combination with a plasmid vector and conversion and based on a CRISPR / Cas9 gene editing technology, SH2D1A is knocked down in theCD8+T cells, genesis of CR8+T cell depletion can be reduced remarkably, the anti-tumor capacity of the depleted CD8+T cells is restored remarkably, and sgRNA can be applied to preparation of anti-tumor medicine.

The invention discloses a TOX gene and application of sgRNA thereof to preparation of an anti-tumour medicament, and relates to the biological field of T cell molecules. By discovery, detection and application of a gene with the most obvious expression difference in CD8+T cells with different depletion degrees and through high-throughput RNA (Ribose Nucleic Acid) sequencing, the invention finds that TOX has an important regulation effect in the occurring and developing process of CD8+T cell depletion, and TOX expression is closely related to occurrence and development of the CD8+T cell depletion; and then the synthetic sgRNA is designed according to a coding sequence of the TOX, the TOX is knocked down in the CD8+T cells by conjugation with a plasmid vector and conversion through a CRISPR / Cas9 gene coding technology, occurrence of the CD8+T cell depletion can be obviously reduced, the anti-tumour ability of depleted CD8+T cells is obviously recovered, and the sgRNA of the TOX gene canbe applied to prepare the anti-tumour medicament.

A method of treating HIV infection comprises administering to a patient a regimen that is able to shut down the immune system in a controlled manner by using T-cell depletion or T-cell modification such that T-cells no longer can be attacked by HIV cells. The T-cell depletor or T-cell modifiers are administered either alone or in combination with 'conventional' anti-HIV drugs.

The present disclosure provides methods of hematopoietic stem cell transplantation (HSCT). In particular, the present disclosure provides a method of HSCT using a combination of an in-vivo T-cell depletion method, with an ex-vivo method of γδ T cell expansion and αβ T cell depletion. The in-vivo T-cell depletion method depletes (in-vivo) the alloreactive T cells that would otherwise increase the risk of GvHD.

A method and an apparatus are provided for determining T-cell repertoire recovery after allo-HSCT or identifying patients at high risk of infection. Combination of 5′-RACE PCR with deep sequencing was used to quantify TCR diversity in 33 individuals using a single oligonucleotide pair. Analysis of duplicate blood samples revealed highly reproducible detection of expanded TCR clonotypes. After 6 months, recipients of cord blood grafts without anti-thymocyte globulin therapy approximated the TCR diversity of healthy subjects, whereas recipients of T-cell-depleted peripheral blood stem cell grafts had a 28-fold and 14-fold lower CD4+ and CD8+ T-cell diversity, respectively. After 12 months, these differences had leveled out for the CD4+, but not the CD8+ T-cell compartment.

A method of treating HIV infection comprises administering to a patient a regimen that is able to shut down the immune system in a controlled manner by using T-cell depletion or T-cell modification such that T-cells no longer can be attacked by HIV cells. The T-cell depletor or T-cell modifiers are administered either alone or in combination with “conventional” anti-HIV drugs.

The invention discloses a fourth-generation CAR-T cell for fusion expression of an I-type IL-10 receptor and a preparation method and application of the fourth-generation CAR-T cell. After CD3 + T cells are infected with lentiviruses expressing fourth-generation CAR structures (scFv-IL10R-CD28-4-1BB-CD3 zeta) through a lentivirus infection method, CD19 scFv-IL10R CAR-T cells capable of recognizingtumor cells in a targeted mode are prepared through enlarged culture. The CD19 scFv-IL10R CAR-T cell is used as a medicine, the antagonism IL-10 immune negative regulation effect of the CD19 scFv-IL10R CAR-T cell is utilized, T cell depletion is relieved, the immunosuppression effect caused by IL-10 is weakened, and the cell is used for killing tumor cell growth in vitro and in vitro in a targeted mode.

The invention provides an anti-PD-1 antibody, a CAR-T cell, and a preparation method and application thereof. The anti-PD-1 antibody comprises LCDR-1-3 as shown in SEQ ID NO: 1-3 and HCDR-1-3 as shown in SEQ ID NO: 4-6, respectively. The CAR-T cell expresses a novel element for efficiently blocking the PD-1, and the element is a single-chain antibody for targeting the PD-1 in a cell membrane anchoring manner. And the chimeric antigen receptor and the cell membrane anchored anti-PD-1 scFv are connected by a 2A cleavage protein. The membrane anchor type anti-PD-1 scFv expressed by the CAR-T cell can almost completely block the expression of PD-1 on the surface of a T cell membrane, and further block a signal channel combined with PD-1 / PD-L1, so that the capability of T cell depletion caused by antagonism tumor of the CAR-T cell is enhanced, and the purpose of enhancing the anti-tumor effect of the CAR-T cell is achieved.

The invention discloses a nano vaccine as well as a preparation method and application thereof. The nano vaccine provided by the invention is prepared by fusing a liposome of which the surface is coupled with an inhibitor of an inhibitory immune checkpoint and a cell membrane of a tumor antigen sensitized dendritic cell cultured by utilizing a tumor cell lysate and keyhole limpet hemocyanin. The obtained nano vaccine is uniform in particle size, the outer layer of the nano vaccine is wrapped by a cell membrane, and the nano vaccine has proper surface potential, size and structural flexibility and is beneficial to aggregation in tumors. After the nano vaccine reaches tumor tissues, antigens can be efficiently and directly presented to T lymphocytes through cell membranes of tumor antigen sensitized dendritic cells, a costimulatory signal necessary for T cell activation is fully provided, meanwhile, T cell depletion can be reversed through an immune checkpoint inhibitor, the function of the inhibited T cells is re-excited, and the T cells are activated. The cytotoxic function and the multiplication capacity of the T cells are effectively and specifically recovered through a double-line strategy.

The invention relates to the field of biomedicine, in particular to a gene for reversing CD8 + T cell depletion to enhance an immunotherapy effect and application of the gene. The invention firstly provides a medicine for reversing or improving the depletion state of CD8 + T cells. The medicine comprises an inhibitor for inactivating or inhibiting UBASH3A gene expression in the CD8 + T cells and / or an inhibitor for reducing the activity of a signal inhibition factor 2. The invention further provides a composition for enhancing the curative effect of anti-PD-1 / PD-L1 immunotherapy, a kit for predicting the effect of anti-T-cell anti-tumor immunotherapy and the like. The invention provides a new tumor immunotherapy target based on the STS2 protein and an application scheme thereof by deeply researching the action mechanism of the STS2 protein in anti-tumor immunotherapy, brings new breakthrough and progress to the field of tumor immunotherapy, and has important scientific significance and clinical application value.

The invention belongs to the technical field of biological medicine, and discloses a medicine for in-vivo engineering CAR-T and a preparation method thereof. The drug provided by the invention comprises a first RNA and a second RNA which are used for coding a chimeric antigen receptor in a specific molar ratio, the second RNA is used for coding at least two cytokines of CCL19, IL-17, IL-15, IL-2 or IL-24, by adopting the drug, the gene delivery efficiency and targeting of in-vivo engineered CAR-T can be improved, better T cell transformation and CAR + T cell generation effects are realized, the CAR-T cell depletion is reduced, and the drug has a good application prospect. According to the present invention, the CAR-T gene is constructed, such that the CAR-T gene can survive for a long time in the tumor microenvironment and continuously provide the treatment effect, has the excellent anti-tumor treatment effect, has the excellent application prospect in the in-vivo engineering CAR-T treatment, and has the important significance on the promotion of the efficient, safe and economical development of the CAR-T treatment.

The present disclosure provides methods of hematopoietic stem cell transplantation (HSCT). In particular, the present disclosure provides a method of HSCT using a combination of an in-vivo T-cell depletion method, with an ex-vivo method of γδ T cell expansion and as T cell depletion. The in-vivo T-cell depletion method depletes (in-vivo) the alloreactive T cells that would otherwise increase the risk of GvHD.

The invention relates to application of a monocarboxylic acid transporter 1 inhibitor in preparation of a medicine for preventing, relieving and / or treating pancreatic cancer. By using the MCT1 inhibitor, the lactic acid level in the pancreatic stellate cells PSCs is effectively reduced, so that the lactic acid of Vps34 is inhibited, and the activation process of autophagy-dependent PSCs mediated by the lactic acid is blocked. By inhibiting the activation of the PSCs, the MCT1 inhibitor further reduces the secretion of downstream chemokines CXCL9 and CXCL10. The CXCL9 and the CXCL10 are key factors for inducing CD8 + T cells to up-regulate PD-1 expression through CXCR3 and STAT3 signal channels, so that the MCT1 inhibitor substantially cuts off an induction signal causing CD8 + T cell depletion on the upstream, further, the in-vivo growth and in-situ tumorigenesis ability of pancreatic cancer can be inhibited, and the purpose of preventing, relieving and / or treating pancreatic cancer is achieved.

A bank of T cells comprising genetically engineered T cells having one or more of the following characteristics compared to non-engineered T cell counterparts: (a) enhanced amplification capacity in culture, (b) enhanced proliferation capacity, (c) reduced apoptosis, and (d) enhanced activation frequency. Such genetically engineered T cells may comprise (i) a mutated gene involved in self-renewal of the cell; (ii) a disrupted gene involved in apoptosis; (iii) a disrupted gene involved in the modulation of T cell depletion; or (iv) a combination of any one of (i)-(iii).

The invention belongs to the technical field of biological medicines, and particularly relates to application of NLRC5 in targeted screening of medicines for improving immunotherapy of esophageal squamous carcinoma. NLRC5 expression is inhibited or regulated, and immunotherapy of esophageal squamous cell carcinoma is improved. The NLRC5 is highly methylated, and the expression of the NLRC5 in the ESCC is reduced. The NLRC5 is over-expressed, immune cell infiltration is promoted, meanwhile, immune escape is promoted by intensifying T cell depletion, immune checkpoint expression is up-regulated, and an immunosuppression state is created, so that anti-tumor immune response is potentially weakened. The invention discloses a polyhedral function of the NLRC5 in immune regulation and control from a single cell level, and particularly discloses close association of the NLRC5 with an immune checkpoint pathway and T cell depletion. A theoretical basis is provided for developing a therapy for targeting NLRC5, and a new way is possibly opened up for enhancing anti-tumor immune response. Researches show that NLRC5 is an important regulatory factor of immune response in ESCC, and plays a dual role in immune activation and immunosuppression.

The invention provides application of ursodesoxycholic acid or a stereoisomer, a prodrug, a crystal form, a pharmaceutically acceptable salt, a pharmaceutically acceptable ester or a pharmaceutically acceptable solvate of ursodesoxycholic acid to preparation of a medicine for treating intrahepatic cholangiocellular carcinoma and a medicine composition for treating the intrahepatic cholangiocellular carcinoma. The invention provides application of ursodesoxycholic acid in treatment of intrahepatic cholangiocellular carcinoma, and application of ursodesoxycholic acid can significantly inhibit growth of tumors and significantly prolong survival time of tested animals. The invention also provides a pharmaceutical composition containing ursodesoxycholic acid and an immune checkpoint inhibitor for treating intrahepatic cholangiocellular carcinoma, and solves the technical problems that in the prior art, an accurate treatment means for reversing CD8 + T cell depletion in intrahepatic cholangiocellular carcinoma is lacked, and an existing treatment method is large in side effect, limited in effect and the like. The invention provides a novel strategy for treating the intrahepatic cholangiocellular carcinoma, and has high clinical application value and wide application prospect.

The invention belongs to the technical field of biological medicines, and particularly relates to a near-infrared two-region fluorine-doped carbon dot nano-enzyme (F-CDs (at) PEG) for photo-thermal enhanced catalytic immunotherapy and a preparation method and application of the near-infrared two-region fluorine-doped carbon dot nano-enzyme (F-CDs (at) PEG). The F-CDs has excellent performance in the aspects of NIR-II fluorescence emission for in-vivo biological imaging and NIR photo-thermal therapy, has photo-thermal enhanced Gox-like, POD-like and GSH-px-like activities, and can be used for destroying energy metabolism and redox balance of tumor cells, enhancing immunotherapy and remodeling a tumor microenvironment. Photo-thermal enhanced immunotherapy induces death of tumor immunogenic cells, and further promotes maturation of antigen presenting cells such as DC, thereby enhancing T cell infiltration in tumors. Besides, the F-CDs (at) PEG reduces the G-CSF level under NIR (808nm) laser irradiation, so that the MDSC level is inhibited, T cell depletion is relieved, and tumor growth is effectively inhibited; the mediated photo-thermal enhanced catalytic immunotherapy can induce strong immune memory, and has a long-term inhibition effect on recurrent tumors.

The invention relates to the technical field of biological medicines, and discloses a preparation method of chlorella vesicles, which comprises the following steps: taking a chlorella solution, and carrying out primary centrifugation at 4 DEG C to obtain primary supernate; carrying out secondary centrifugation on the primary supernate at 4 DEG C to obtain secondary supernate; carrying out third centrifugation on the secondary supernatant, and discarding the supernatant to obtain a chlorella vesicle precipitate; the invention also discloses an application of the chlorella vesicle in relieving T cell depletion. The invention provides an immunotherapy preparation with active chlorella vesicles, aiming at the problems of chronic infection and T cell depletion in a tumor microenvironment, the immunotherapy preparation relieves ammonia accumulation in the tumor microenvironment through ammonia metabolism, regulates the ammonia metabolism process in the tumor microenvironment, relieves the inhibition effect on T cells, and improves the immunotherapy effect of the tumor microenvironment. The T cell depletion state is reversed to a certain extent.

The invention discloses a sustained-release drug-loaded microsphere and a preparation method and application thereof, the sustained-release drug-loaded alginate microsphere prepared by a freeze spray drying method has good dispersibility and stability in an aqueous solution, and can effectively release loaded active components. After being injected into a tumor in situ, the hyaluronidase and the chemotactic factor can be released in a long-acting manner, the number and functions of the infiltrating T cells in the tumor are increased, the anti-tumor effect of the infiltrating T cells is effectively improved, and the T cell depletion is improved. Therefore, the time and the cost of lymphocyte in-vitro culture are shortened, and the curative effect of the tumor infiltration lymphocyte therapy is enhanced. After T lymphocytes are transfused back, sustained-release drug-loaded microspheres are injected in situ, so that the collection efficiency of the T cells at a tumor part and the activity of the T cells can be improved, the transfused T cells can play an anti-tumor role, and the curative effect is enhanced.