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Method for treating side effect of chimeric antigen receptor (CAR) T cell therapy

A cell therapy, side effect technology, applied in receptors/cell surface antigens/cell surface determinants, antibodies, animal cells, etc., can solve the problems of subject death and incomplete success

Inactive Publication Date: 2020-01-10
CYNATA THERAPEUTICS LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although these side effects have been managed with varying degrees of success, they have not been completely successful, and adverse events have occurred with regularity in many clinical trials, and some subjects have even died

Method used

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  • Method for treating side effect of chimeric antigen receptor (CAR) T cell therapy
  • Method for treating side effect of chimeric antigen receptor (CAR) T cell therapy
  • Method for treating side effect of chimeric antigen receptor (CAR) T cell therapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0127] Example 1. CAR and retroviral vectors

[0128] All CARs in these examples comprised scFv derived from the J591 hybridoma specific for prostate-specific membrane antigen (PSMA) as described (Gong, M.C. et al. Neoplasia 1, 123-127 (1999)). sex. To facilitate detection of transduced cells, all constructs contained the encephalomyocarditis virus internal ribosome entry site (EMCV-IRES) and the eGFP gene inserted into the SFG vector. In Pz1, J591 scFv(P) is coupled to the intracellular domain of human TCRζ(z) through the human CD8α hinge and transmembrane sequence (Gong et al.). P28 comprises a fusion of J591 scFv (P) to human CD28 (28) as described (Krause, A. et al. J. Exp. Med. 188, 619-626 (1998) and Krause, A. et al. Mol. Ther. 1 , S260, 713 (2000)). To construct P28z, primers 5'-GGCGGCCGCAATTGAAGTTATGTATC-3' (SEQ ID NO: 1) and 5'-TGCGCTCCTGCTGAACTTCACTCTGGAGCGATAGGCTGCTAAGTCGCG-3 (SEQ ID NO: 2) were used to amplify nucleotides 336-660 of CD28. The intracellular dom...

Embodiment 2

[0129] Example 2. Culture and Retroviral Transduction of Primary Human T Cells

[0130] Peripheral blood mononuclear cells from healthy donors were established in RPMI+10% (vol / vol) human serum, activated with lectin (2 μg / ml) for two days, and transferred to cells pre-coated with Retronectin (15 μg / ml; Non-tissue culture plates (FALCON, Becton Dickinson, Franklin, Lakes, N.J.) from Takara Biomedicals, Shiga, Japan). Gibbon leukemia virus envelope pseudotyped retroviral particles comprising the CAR construct were generated as described (Gallardo, H.F. et al. Blood 90, 952-957 (1997) and Rivière, I. et al. Mol. Biotechnol. )).

[0131] Three days after transduction of mitogen-activated PBLs, gene transfer efficiencies ranged from 20% to 70%. CD4 + and CD8 + T cell subsets were transduced with similar efficiency. Expression of fusion receptors comprising the zeta chain was also analyzed by Western blot, demonstrating the formation of homodimers and little, if any, heterodim...

Embodiment 3

[0132] Example 3. CD19-specific scFv

[0133] To construct CD19-specific scFv, the heavy (VH) and light (VL) chain variable regions were cloned from the hybridoma cell line SJ25C1 using degenerate primers as described (Orlandi et al. Proc Natl Acad Sci USA 86, 3833-3837 (1989)). Combine these coding regions with coding (Gly 3 Ser) 4 The DNA fragments of the spacer are fused. A co-stimulatory signaling element (including transmembrane and extracellular portion) (SEQ ID NO:7) from human CD28 was ligated to the 3' end of the resulting scFv, and the cytoplasmic domain of human ζ (SEQ ID NO:8 ) to the 3' end of the CD28 portion to form the fusion gene 19-28z.

[0134]The 19-28z fusion was tested for its ability to reduce tumor growth and enhance survival in mice injected with NALM6T cells. NALM6 cells express CD19, MHC I, and MHC II, but not B7.1 or B7.2. Most (approximately 80%) of untreated SCID-Beige mice developed hindlimb paralysis 4-5 weeks after tumor cell injection, a...

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Abstract

The invention relates to a method for treating a side effect of chimeric antigen receptor (CAR) T cell therapy, the method comprising administering a mesenchymal stem cell (MSC) to a subject who has been or is being administered CAR T cell therapy.

Description

technical field [0001] The present invention relates to the treatment of side effects of chimeric antigen receptor (CAR) T cell therapy. Background technique [0002] Immunotherapy is a type of biological therapy designed to improve a subject's natural immune system to fight disease. In general, immunotherapy refers to cancer immunotherapy. [0003] A growing area of ​​cancer immunotherapy is adoptive cell transfer (ACT), in which T cells are isolated, engineered to recognize and attack cancer cells, and then expanded and reintroduced into a subject with cancer. This may involve isolating and engineering a subject's own T cells for autologous ACT, but the use of donor T cells for allogeneic (sometimes called syngeneic) ACT is also being investigated. [0004] For ACT, T cells or NK cells are engineered to express receptors that recognize antigens expressed on cancer cells. The receptor may be a T cell receptor (TCR) or a chimeric antigen receptor (CAR). T cells that expr...

Claims

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Application Information

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IPC IPC(8): A61K35/28A61K39/00C12N5/0775C07K16/46A61K45/08A61P35/00A61P35/02A61P37/06
CPCA61K35/28A61P37/06A61P35/00A61P35/02C07K14/7051C07K16/2803C07K16/2809C07K16/2866C07K16/3069A61K2039/505A61K2039/507C07K2317/622C07K2319/03C07K2319/33A61K2039/884C07K14/70517C07K14/70521C07K2319/30A61K39/464495A61K2239/48A61K39/4631A61K2239/31A61K39/464412A61K39/4611A61K39/464471A61K2239/38A61K2300/00A61P37/00C12N5/0662C12N2500/12C12N2501/115C12N2510/00
Inventor K·凯利I·斯卢克文
Owner CYNATA THERAPEUTICS LTD
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