Synergistic and depletion-resistant chimeric antigen receptor T cell and application thereof in preparation of medicine for treating tumors

Abstract

The invention discloses a synergistic and depletion-resistant chimeric antigen receptor T cell and application thereof in preparation of a medicine for treating tumors. The synergistic and depletion-resistant chimeric antigen receptor T cell comprises an antigen binding structural domain (scFv) and a signal transduction structural domain, wherein the signal transduction structural domain comprises a first transduction structural domain and a second transduction structural domain, and the antigen binding structural domain is connected in series between the first transduction structural domain and the second transduction structural domain; the first conduction structural domain comprises a receptor signal structural domain and / or a costimulatory structural domain; the second conductive domain comprises a transmembrane structural domain DAP12, and the transmembrane structural domain DAP12 is or is not linked to the costimulatory structural domain and / or an elementary signal domain. According to the T cell expressing the chimeric antigen receptor, the chimeric antigen receptor can be more efficiently and stably expressed in the T cell, so that a killing effect on a target cell can be better played, the durability of CAR-T is improved, the expression of a depletion marker is lower, and the memory type T cell is richer.

Description

technical field [0001] The invention belongs to the field of biology, and in particular relates to a chimeric antigen receptor T cell with synergistic and anti-exhaustion and its use in the preparation of drugs for treating tumors. Background technique [0002] In recent years, although conventional tumor treatment methods such as radiotherapy, chemotherapy, and surgery can achieve certain therapeutic effects, the problems of tumor metastasis, recurrence, and low survival rate of patients have not been properly resolved. With the development of tumor immunology theory and technology, the role of immune cells in tumor treatment has been paid more and more attention. Among them, chimeric antigen receptor T cell technology is a cell therapy technology that has developed very rapidly in recent years. [0003] Chimeric antigen receptor (CAR) is the core component of CAR-T. Using the ligand-binding domain properties, CAR can redirect the specificity and reactivity of selected imm...

AI Technical Summary

Problems solved by technology

[0004] There are still some problems in the current traditional CAR-T for hematological tumors, which limit its clinical application

The currently FDA-approved CD19 CAR-T cell drugs use CD28 or 4-1BB as costimulatory domains respectively (Forsberg MH, et al. The potential of CAR T therapy for relapsed or refractory pediatric and young adult B-cell ALL.Ther Clin Risk Manag ,2018,14:1573-1584.Hombach AA,et al.Theweal and woe of costimulation in the adoptive therapy of cancer with chimericantigen receptor (CAR)-redirected T cells.Curr Mol Med,2013,13(7):1079- 1088.) The two CAR-T cells have their own advantages and disadvantages. The CAR-T cells with the costimulatory domain of CD28 proliferate faster in the early stage of the response, and can mediate stronger tumor killing capabilities, but at the same time have stronger side effects , and the persistence in the late stage of the immune response is poor; while the proliferation ability of 4-1BB-based CAR-T cells is poorer than that of CD28 CAR in the early stage of the response, but the persistence is better, and it can also maintain a high level in the late stage of the immune response Cell number (Salter AI, et al. Phosphoproteomic analysis of chimeric antigen receptor signaling reveals kinetic and quantitative differences that affect cell function. Sci Signal, 2018, 11(544): eaat6753. Maloney DG. Anti-CD19 CAR T cell therapy for lymphoma-off to theraces!.Nat Rev Clin Oncol,2019,16(5):279-280.Kawalekar OU,et al. Distinct signaling by chimeric antigen receptors(CARs) containing CD28 signaling domainversus 4-1BB in primary human T cells.Blood,2013 ,122(21):2902.)

In addition, it is worth noting that CAR-T cells also have some side effects during treatment, such as cytokine release syndrome (Cytokine release syndrome, CRS), neurotoxicity, loss of B cell function, and tumor recurrence (Bonifant CL, et al.Toxicity and management in CAR T-cell therapy.Mol Ther-Oncolytics,2016, 3:16011.Porter DL,et al.Chimeric antigen receptor T cellspersist and induce sustained remissions in relapsed refractory chroniclymphocytic leukemia.Sci Transl Med ,2015,7(303): 303ra139.Maude SL,etal.Managing cytokine release syndrome associated with novel T cell-engaging therapies.Cancer J,2014,20(2):119-122.Sadelain M.Chimeric antigen receptors: a paradigm shift in immunotherapy. Annu Rev Canc Biol, 2017, 1:447-466.)

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