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Improved T cell therapy

A cellular and therapeutic technology, applied in genetically modified cells, gene therapy, animal cells, etc., can solve the problem of not being able to fundamentally promote the immune memory of CAR-T cells

Active Publication Date: 2019-11-05
IMMUNOTECH BIOPHARM CO LTD +3
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] Although the development of new CAR structures and the precise determination of the source of CAR-T cells may help to improve the application of CAR-T, these strategies cannot fundamentally promote the generation of immune memory of CAR-T cells, which is critical for adaptation. Sexual immune response is essential

Method used

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Experimental program
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Effect test

Embodiment 1

[0113] Embodiment 1, the production and characterization of Raji-B-NDG mouse model

[0114] Nonobese diabetic severe combined immunodeficiency (NOD-scid) mice with null Il2rg lack mature T, B, and natural killer (NK) cells and lack cytokine signaling, leading to better engraftment of multiple cancer types . In this embodiment, the Il2rg gene was deleted from NOD-scid mice using CRISPR / Cas9 genome editing technology, thereby preparing B-NDG mice ( figure 1 A). B-NDG mice were observed to be viable, fertile and did not display any obvious physical abnormalities. Compared with NOD-scid mice, FACS analysis showed that the spleen and peripheral blood of B-NDG mice had lower numbers of CD19+ B cells, CD4+ and CD8+ T cells ( figure 1 B). NOD-scid mice had a high percentage of CD49b+ NK cells (spleen 20.90%, peripheral blood 24.10%), while B-NDG mice had no functional NK cells (spleen 1.45%, peripheral blood 5.95%). Therefore, B-NDG mice generated by genome editing are phenotypic...

Embodiment 2

[0117] Example 2, In vitro and in vivo efficiency of CD19-targeted CAR-T cells

[0118] After T cell activation, PBMCs isolated from volunteers were treated with second-generation CAR ( figure 2 A) Perform transduction. The results showed that the proportion of CD19CAR-T cells increased with the prolongation of culture time, reaching 20% ​​at D12, and the total number of cells was greater than 1×10 at D10 after infection. 8 ( figure 2 B). When co-cultured with CD19+ Raji cells in vitro, CD19CAR-T cells cultured for 12 days showed more than 50% killing effect on Raji cells when the effector cell / target cell ratio was about 3:1. In order to further verify the anti-tumor effect of CD19CAR-T cells in vivo, B-NDG mice were injected with 5×10 5 Raji-Fluc cells, followed by implantation of 2 × 10 7 CD19CAR-T cells. After four days of CD19CAR-T treatment (D9), the bioluminescent signal of these treated mice was close to that of uninoculated mice ( image 3 A), showing that CD...

Embodiment 3

[0119] Embodiment 3, the recurrence source of Raji tumor

[0120] Although CAR-T cells were effective, B-NDG mice eventually died of tumors. To find the source of the Raji cell relapse, all major organs of the mice were tested for bioluminescence. The results showed that Raji cells were significantly cleared by CD19CAR-T cells in spleen, heart and skin. For example, in the spleen, bioluminescence was reduced by 1000-fold after CAR-T cell treatment ( image 3 A). However, CD19CAR-T was not as effective in other organs, especially in the liver and brain ( image 3 A). Residual Raji cells hidden in these organs that cannot be effectively cleared by CAR-T may be the cause of tumor recurrence.

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Abstract

The invention belongs to the field of biomedicine, particularly relates to an improved T cell therapy, and more particularly relates to a therapy which enhances the cancer therapy efficacy of therapeutic T cells (such as CAR-T or TCR-T cells) by stimulation with living cells expressing cancer associated antigens.

Description

technical field [0001] The invention belongs to the field of biomedicine. In particular, the present invention relates to improved methods of T cell therapy. More specifically, the present invention relates to enhancing the cancer treatment efficacy of therapeutic T cells, such as CAR-T or TCR-T cells, by stimulation with living cells expressing cancer-associated antigens. [0002] Background of the invention [0003] Currently, multiagent chemotherapy regimens and / or targeted therapy have achieved high rates of complete remission in pediatric patients with B-cell acute lymphoblastic leukemia (B-ALL), but in adults still have a poor prognosis and relapsed / refractory Sexual B-ALL is a big challenge for all patients. Lymphocyte-depleting chemotherapy followed by CD19-targeted chimeric antigen receptor-modified T (CAR-T) cell therapy is a novel treatment approach and has been shown to be effective in adults and children with relapsed / refractory B-ALL, chronic There was a stro...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K39/00A61K35/17A61P35/00A61P35/02
CPCA61K39/0011A61K35/17A61P35/00A61P35/02A61K2039/5152A61K2039/5156C12N2501/515C12N5/0638C12N2510/00C12N5/0093A61K39/001112A61K2039/5158A61K2039/804C07K14/7051C07K2319/03A61K2039/5154A01K2227/105A01K2217/075A01K2267/03A01K2207/12A61K48/00C12N2740/16043A61P35/04A61K38/177A61K38/1774A61K2039/505A61K2039/545C07K16/2803C07K2317/622
Inventor 王歈李贤秀郑南哲王佑春孙磊刘强张永华王萌
Owner IMMUNOTECH BIOPHARM CO LTD
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