Application of injectable microsphere system in preparation of drug carrier for activating and amplifying tumor infiltrating T cells

Abstract

The invention discloses application of an injectable microsphere system in preparation of a drug carrier for activating and amplifying tumor infiltrating T cells. A microsphere preparation method comprises the following steps: (1) preparing porous microspheres; (2) preparing nano particles entrapped with cell factors; (3) grafting nano particles entrapped with cytokines on the surfaces of the porous microspheres through amido bonds; and (4) grafting the antibody to the surface of the porous microsphere through a dopamine group. The microspheres can achieve slow release of cell factors; the infiltrating T lymphocytes locally existing in the tumor are amplified to resist the inhibition effect of the tumor microenvironment; by utilizing the broad-spectrum TCR advantage of TIL-T on tumor specific antigens, specific killing can be realized, and antigen loss and off-target effects are avoided; compared with an immune checkpoint blocking method, since dual signals can be provided, the injectable microsphere system can activate TIL-T without limitation. The memory phenotype formed by the microsphere system can endow the organism with lasting anti-tumor immunity and prevent relapse.

Description

Technical field [0001] The present invention belongs to the technical field of biomedical materials, and more particularly to an injectable microsphere system in the manufacture of a pharmaceutical carrier for activating, amplifying tumor infiltration T cells. Background technique [0002] In the past 10 years, the immunotherapy strategy of tumors has been rapidly developed. The immunotherapy is a targeted method for treating cancer. The principle is to use the immune response of the tumor-related antigen to activate the body, and then inhibit tumor development, transfer and recurrence. T cell-mediated cellular immunity is the main force of anti-tumor immunity, currently in T cell-centric immunotherapy mainly includes transduction cytopathic (ACT) and immunoaffinition blocking. It has been reported that the adverse metastasis of tumor-specific T cells can cause leukemia or melanoma patients to regain the tumors and even last-lasting responses, however, the immunosuppressive micro...

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Problems solved by technology

It has been reported that the adoptive transfer of tumor-specific T cells can cause tumor regression and even durable responses in patients with leukemia or melanoma. However, CAR-T therapy, as the hottest topic in recent years, has been constantly innovating, and has been updated to four generations in the past ten years. Its prospect is undeniable, but we must also face the current situation. Disadvantages of CAR-T technology: off-target effect, difficult to enter the tumor, single antigen target, recurrence caused by loss of tumor antigen, etc.

There is partial lymphocyte infiltration in the tumor microenvironment of solid tumors. Among them, tumor-infiltrating T cells (TIL) have good infiltration and a broad spectrum of TCRs that recognize tumor-specific antigens, which can well make up for the current CAR-T cells. Faced with these difficulties in therapy, immune checkpoint antibodies such as PD-1 have achieved significant curative effects in the treatment of solid tumors such as lung cancer by releasing the anti-tumor immunity of tumor-infiltrating T cells, but their low response rate limits their development. The highest rate of lung cancer is only about 20%, mainly due to the lack of MHC-I molecules and the occurrence of T cell exhaustion

Tumor-infiltrating T cells play an important anti-tumor role in tumor immunity, but problems such as low numbers and rapid exhaustion in local tumors limit the tumor-killing effect of tumor-infiltrating T cells

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