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Joint use of immunologic effector cells and radiation in tumor treatment

An immune effector cell and radiation therapy technology, applied in the field of tumor therapy, can solve the problems of affecting the effect of adoptive immune cell therapy, ineffective CAR-T cells, and patient death.

Pending Publication Date: 2019-06-21
CRAGE MEDICAL CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] However, lymphoid pretreatment may also affect the effect of adoptive immune cell therapy, and may participate in the formation of cytokine storm, and may also cause severe myelosuppression and other toxic reactions, especially in the treatment of solid tumors, after lymphatic pretreatment The curative effect of CAR-T cells is not significant (Zhang et al., "Phase I Escalating-Dose Trial of CAR-T Therapy Targeting CEA+Metastatic Colorectal Cancers", Molecular Therapy (2017), 25(5):1248-1258), and It was also reported that a cytokine storm occurred during the treatment of metastatic colon cancer with lymphoid preconditioning plus ERBB2-CAR-T, resulting in death of the patient (Molecular Therapy vol.18 no.4,843–851apr.2010)

Method used

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  • Joint use of immunologic effector cells and radiation in tumor treatment
  • Joint use of immunologic effector cells and radiation in tumor treatment
  • Joint use of immunologic effector cells and radiation in tumor treatment

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0128] Example 1 Construction of CAR-T cells and establishment of mouse model of clearing lymphoma

[0129] (1) Construction of CAR-T cells

[0130] As an example, this embodiment uses a second-generation CAR targeting EGFRvIII. To meet the needs of animal experiments, this embodiment uses mouse gene sequences to construct the transmembrane domain and intracellular domain of CAR.

[0131] The coding sequence of the mouse CD8α signal peptide (SEQ ID NO: 1), the coding sequence of the monoclonal antibody capable of recognizing human activated EGFR and human EGFRvIII (SEQ ID NO: 2), the mouse CD8α hinge region and The coding sequence of the transmembrane region (SEQ ID NO: 3), the coding sequence of the murine CD28 intracellular domain (SEQ ID NO: 4), and the coding sequence of the murine CD3ζ intracellular domain (SEQ ID NO: 5) were sequentially connected, and the in vitro gene The EGFRvIII-m28Z gene fragment was obtained by a synthetic method, and the IRES-GFP fragment in the ...

Embodiment 2

[0138] Example 2 Anti-tumor therapeutic effect of local tumor radiation therapy combined with EGFRvIII-m28Z CAR-T cells on colon cancer subcutaneous xenografts

[0139]Since the EGFR287-302 epitope is only exposed in EGFRvIII or tumors overexpressing EGFR, the epitope is hidden in normal tissues (Gan HK et al., Targeting of a conformationally exposed, tumor-specific epitope of EGFR as a strategy for cancer therapy. Cancer Res, 2012, 72(12): 2924-2930.). Therefore, the CT26 cell model of mouse EGFR (CT26-EGFRvIII) overexpressing the chimeric human EGFR amino acid epitope 287-302 and removing exons 2-7 of mouse EGFR was established by conventional means of molecular biology. CT26 cells were purchased from the American Type Culture Collection (ATCC CRL-2638).

[0140] (1) Establishment of mouse colon cancer model and group treatment:

[0141] Firstly, the mice were divided into two groups: the non-clearing stranguria group and the clearing stranguria group.

[0142] Unclean dr...

Embodiment 3

[0157] Example 3 Detection of IFN-γ concentration in mouse colon cancer model treated with local tumor radiation therapy and EGFRvIII-m28Z CAR-T

[0158] Get the mouse plasma 50 μ l of the 8th day (Day21) after starting treatment among the embodiment 2, measure the level of the interferon gamma in the blood with the ELISA kit of Lianke Biological Company, the result is as follows Figure 5 As shown, there was no significant difference between the EGFRvIII-m28Z+X-ray group and the CAR-T treatment group after clearing the lymphatic pretreatment group in the combination group of mice with unclear lymphoma, while the X-ray+EGFRvIII-m28Z group interferon-γ The concentration was the highest, which was higher than that of the CAR-T treatment group after Qinglin pretreatment (P<0.05, Oneway ANOVA). The above results indicate that CAR-T cell therapy combined with local tumor radiation therapy can promote the secretion of interferon-γ, and its promotion level can reach the level of the ...

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Abstract

The invention relates to a tumor treatment method and particularly provides joint use of immunologic effector cells and radiation in tumor treatment, and a method of treating an individual with tumorsby joint use of immunologic effector cells and local radiation. The method provides no lymphocyte removal for the individual; the immunologic effector cells comprise a receptor to recognize tumor antigens to tumors. Tests prove that the method provided herein has significant antitumor effect for solid tumors; at the premise of pretreatment without removing lymphocytes, the joint treatment of CAR-T cell therapy and local radiotherapy with no lymphocyte removal helps attain better treatment effect than CAR-T treatment with lymphocyte removal; antitumor treatment effect is improved greatly.

Description

technical field [0001] The invention belongs to the field of immunotherapy, and specifically relates to the combined application of immune effector cells with receptors targeting tumor antigens and triggering cell activation and tumor local radiation therapy for tumor treatment. Background technique [0002] Adoptive immune cell therapy, such as chimeric antigen receptor-modified T lymphocyte (CAR-T) therapy, is expected to become an important treatment for tumors, especially malignant tumors, but the immune effector cells used still face the challenge of how to expand and improve in vivo. Antitumor activity and other issues. [0003] Existing literature has shown that lymphocyte depletion (lymphocyte clearing) pretreatment can increase the in vivo expansion of immune effector cells such as CAR-T cells or TIL and their anti-tumor activity, and recently by treating large-scale CD19-CAR-T cells in blood The analysis of clinical experimental data of malignant tumors found that...

Claims

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Application Information

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IPC IPC(8): A61K35/17A61N5/10A61P35/00A61P35/04A61K35/15
CPCA61K41/00A61N5/10A61P35/00A61P35/04C07K16/28C07K19/00C12N5/10A61K2239/38A61K39/4631A61K39/4611A61K2239/31A61K39/464404A61K2239/49A61K2239/50
Inventor 李宗海周敏
Owner CRAGE MEDICAL CO LTD
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