CN104789595A - Construction method of chimeric antigen receptor double-negative T cell - Google Patents
Construction method of chimeric antigen receptor double-negative T cell Download PDFInfo
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Abstract
The invention discloses a construction method of a chimeric antigen receptor double-negative T cell. The construction method comprises the following steps: according to characteristics of CD3<+>/CD4<->/CD8<->double-negative T cell, selecting the purified CD3<+>/CD4<->/CD8<->double-negative T cell in vitro, and utilizing the synergistic principle of multiple cell factor signal channels and a TCR signal channel to screen out an in-vitro culture scheme suitable for activation and virus transfection of the double-negative T cell. The in-vitro culture scheme can quickly and controllably activate the double-negative T cell, expresses the specific chimeric antigen receptor on the double-negative T cell through a lentiviral transfection technology at high efficiency, preparing a CAR-DN-T cell, enables the CAR-DN-T cell to specifically identify the tumor cell corresponding to the chimeric antigen receptor, promotes the CAR-DN-T cell to be further activated and proliferated, and quickly kills and wounds the tumor cell. According to the construction method disclosed by the invention, the prepared CAR-DN-T cell is from homologous variants of other healthy donators, so that the preparation of the cell gets rid of limitation of the current illness situation of a patient, the cell can be prepared on a large scale in advance, and the patient can be subjected to low-dosage re-transfusion treatment for multiple times according to the clinical diagnosis result at any time.
Description
Technical field
The present invention relates to biomedicine field, in particular to a kind of construction process of Chimeric antigen receptor double negative t cells, particularly relate to a kind of Chimeric antigen receptor CD3
+/ CD4
-/ CD8
-the construction process of double negative t cells.
Background technology
Chimeric antigen receptor T cell (CAR-T cell) technology, utilize genetically engineered and virus transfection technology to build an ectogenic Chimeric antigen receptor to killer T cell, make it can specific recognition tumor markers, and promoting CAR-T cell proliferation, activation, persistence plays the technology of tumor-killing function.Because it is to CD19
+the clinical test results of the brilliance of B-lineage Acute Lymphocyte Leukemia, has caused the extensive concern of medical circle, is considered to the therapy being hopeful most to cure tumour.
But, current CAR-T clinical trial is all in autologous patient, isolate the preparation that T cell carries out CAR-T cell, this just proposes very high requirement to the T cell quality of patient, clinical application accounts for the ratio of PBMC, T cell propagation and activation capability to the T cell of patient, and the killing ability etc. of T cell all has higher serviceability standards.Find in clinical trial practice, the T cell of the patient more than 80% does not reach requirement prepared by CAR-T cell, and therefore Most patients cannot be benefited from existing CAR-T treats.In view of this problem, the preparation of homology Hetersomata CAR-T becomes the focus of research.
A current research direction is after the φt cell receptor (TCR) of the T cell of homology xenogenic origin being knocked out (TCR-KO) by gene Knockout, it is made to lose the characteristic of MHC restriction, then the T cell that TCR knocks out is purified into, carry out the preparation of CAR-T cell again, make it play tumor-killing effect and avoid causing graft versus host disease (GVHD).But run into very large technical bottleneck in actual applications, major cause is comparatively large for the carrier molecule amount such as CRISPR-Cas9 of gene Knockout, imports the inefficiency of T cell difficulty, its gene knockout.Further, if use the mode of virus transfection to import the carriers such as CRISPR-Cas9, there will be again the resistance phenomenon of Chimeric antigen receptor secondary virus transfection, therefore TCR-KO-CAR-T cell yield is extremely low, and can not prepare on a large scale, applicability is poor.
Summary of the invention
The object of the invention is to the above problem overcoming prior art existence, a kind of construction process of Chimeric antigen receptor double negative t cells is provided, utilizes CD3
+/ CD4
-/ CD8
-the antitumor properties of double negative t (DN T) cell and the non-limiting of major histocompatibility antigen (MHC), in conjunction with existing Chimeric antigen receptor technology, construct a kind of novel Chimeric antigen receptor double negative t cells (CAR-DN-T).DN-T cell can separation and purification from normal human peripheral blood, and the uniqueness utilizing us to create activates and virus transfection mode, can make specific Chimeric antigen receptor in its transfection efficiently, the tumour cell of specific killing Chimeric antigen receptor identification.It is restricted that CAR-DN-T cell prepared by experimental data display does not have MHC, graft versus host disease (GVHD) can not be caused, Chimeric antigen receptor T cell (CAR-T cell) clinical treatment carrying out homology allosome formula in other eligible patients's bodies can be fed back to, be a kind of novel CAR-T cell, can carry out fast promoting and industrialization.
For realizing above-mentioned technical purpose, reach above-mentioned technique effect, the present invention is achieved through the following technical solutions:
A construction process for Chimeric antigen receptor double negative t cells, according to CD3
+/ CD4
-/ CD8
-the characteristic of double negative t cells, the external CD3 sub-electing purifying
+/ CD4
-/ CD8
-double negative t cells, utilize cytokine profiles signal path and the synergistic principle of TCR signal path, filter out the vitro culture scheme being suitable for double negative t cells activation and virus transfection, activation double negative t cells that can be quick, controlled, and specific Chimeric antigen receptor slow-virus transfection technique to high-efficiency rate is expressed on double negative t cells, prepare CAR-DN-T cell, can tumour cell corresponding to specific identification Chimeric antigen receptor, promote further activation and the propagation of CAR-DN-T cell, and quick killing tumor cell.
Further, described external sorting schemes is, utilizes the negative sorting of CD4/CD8 biotin labelled antibodies and CD3/CD28 marked by magnetic bead antibody positive sorting conbined usage, sub-elects highly purified CD3
+/ CD4
-/ CD8
-double negative t cells, then adds the cytokine mixed solution stimulation of specific proportioning mixing, cultivates and carry out Chimeric antigen receptor virus transfection after 72 hours, obtain a high proportion of CAR-DN T cell to the double negative t cells of purifying.
Preferably, described cytokine mixed solution comprises: IL-2, IL-15, GMCSF, TNF α, IFN γ.
The invention has the beneficial effects as follows:
1, the present invention is first by CD3
+/ CD4
-/ CD8
-double negative t (DN T) cell is applied in the clinical application of CAR-T cell as mother cell, utilizes that the MHC's of DN-T cell is non-limiting, develops novel CAR-DN-T cell and is applied to homology allosome clinical treatment.The CAR-DN-T cell of preparation, other healthy contributors (comprising families of patients etc.) of homology allosome can be derived from, therefore the restriction of patient's disease condition has instantly been broken away from the preparation of this cell, can shift to an earlier date and prepare on a large scale, and according to clinical diagnoses, low dosage, repeatedly adoptive therapy are carried out to patient at any time, can while meeting its curative effect, the multiple toxic side effect that effective control CAR-T cell may bring out, reduces the Clinical practice risk of CAR-T cell.
2, the activation scheme of the novel DN-T cell of the present invention's establishment, cytokine profiles and φt cell receptor combined stimulation scheme, can promote the transfection efficiency of Chimeric antigen receptor virus to greatest extent, improves the preparation efficiency of CAR-DN-T cell.
3, CAR-DN-T cell can derive from the CD3 of healthy human peripheral blood
+/ CD4
-/ CD8
-double negative t (DN T) cell, because healthy contributor's immunity system perfects, the activation of the CAR-DN-T cell of this kind of homology allosome, propagation and killing ability are all better than the CAR-T cell in autologous patient source, and tumor-killing ability is stronger.
Above-mentioned explanation is only the general introduction of technical solution of the present invention, in order to better understand technique means of the present invention, and can be implemented according to the content of specification sheets, coordinates accompanying drawing to be described in detail as follows below with preferred embodiment of the present invention.The specific embodiment of the present invention is provided in detail by following examples and accompanying drawing thereof.
Accompanying drawing explanation
Accompanying drawing described herein is used to provide a further understanding of the present invention, and form a application's part, schematic description and description of the present invention, for explaining the present invention, does not form inappropriate limitation of the present invention.In the accompanying drawings:
Fig. 1 is CD3
+/ CD4
-/ CD8
-double negative t cells schematic diagram;
Fig. 2 is CD3
+/ CD4
-/ CD8
-the sorting of double negative t cells, activation and Chimeric antigen receptor virus transfection schema;
Fig. 3 is that cytokine profiles and φt cell receptor combined stimulation scheme effectively promote double negative t cells virus transfection efficiency comparative;
Fig. 4 is autologous CAR-CD8-T cell and homology allosome CAR-DN-T cells in vitro fragmentation test figure mono-;
Fig. 5 is autologous CAR-CD8-T cell and homology allosome CAR-DN-T cells in vitro fragmentation test figure bis-;
Fig. 6 is CAR-T-19 and CAR-DN-T cell therapy mouse-people CD19+Raji B cell lymphoma follow board living imaging.
Fig. 7 is CAR-T-19 and CAR-DN-T cell therapy mouse-people CD19+RajiB cell lymphoma follow board survival curve.
Embodiment
Below with reference to the accompanying drawings and in conjunction with the embodiments, describe the present invention in detail.
In view of reaching its maturity of current C AR-T cell therapy, its clinical validity also highlights gradually, therefore, breaks through the individuality restriction of CAR-T cell therapy, can mass-producing and industrialization be urgent problem instantly.Existing research finds, there is a group CD3 in the peripheral blood of normal people
+/ CD4
-/ CD8
-double negative t (DN T) cell, with reference to shown in Fig. 1, account for the 1-5% of periphery blood T lymphocyte, it has nonspecific tumor-killing function, and do not possess major histocompatibility antigen (MHC) restriction, graft versus host disease (GVHD) can not be caused.
The present invention is according to CD3
+/ CD4
-/ CD8
-the characteristic of double negative t (DN T) cell, the external CD3 sub-electing purifying
+/ CD4
-/ CD8
-double negative t (DN T) cell, utilize cytokine profiles signal path and the synergistic principle of TCR signal path, filter out the vitro culture scheme being suitable for DN-T cell-stimulating and virus transfection, activation DN-T cell that can be quick, controlled, and specific Chimeric antigen receptor slow-virus transfection technique to high-efficiency rate is expressed on DNT cell, prepare CAR-DN-T cell, can tumour cell corresponding to specific identification Chimeric antigen receptor, promote further activation and the propagation of CAR-DN-T cell, and quick killing tumor cell.
Wherein, sorting schemes utilizes the negative sorting of CD4/CD8 biotin labelled antibodies and CD3/CD28 marked by magnetic bead antibody positive sorting conbined usage, sub-elect highly purified CD3+/CD4-/CD8-double negative t (DN T) cell, then the DN-T cell of purifying is added to cytokine mixed solution (comprising IL-2, IL-15, GMCSF, TNF α, IFN γ) stimulation of specific proportioning mixing, cultivate and carry out Chimeric antigen receptor virus transfection after 72 hours, obtain a high proportion of CAR-DN T cell, with reference to shown in Fig. 2.
Meanwhile, we have also founded the scheme that CAR-DN-T cells in vitro increases on a large scale, and it can be increased more than 4000 times, reach the ability of extensive preparation, make homology allosome CAR-DN-T cell therapy become possibility.
The present invention is first by CD3
+/ CD4
-/ CD8
-double negative t (DN T) cell is applied in the clinical application of CAR-T cell as mother cell, utilizes that the MHC's of DN-T cell is non-limiting, develops novel CAR-DN-T cell and is applied to homology allosome clinical treatment.The CAR-DN-T cell of preparation, other healthy contributors (comprising families of patients etc.) of homology allosome can be derived from, therefore the restriction of patient's disease condition has instantly been broken away from the preparation of this cell, can shift to an earlier date and prepare on a large scale, and according to clinical diagnoses, low dosage, repeatedly adoptive therapy are carried out to patient at any time, can while meeting its curative effect, the multiple toxic side effect that effective control CAR-T cell may bring out, reduces the Clinical practice risk of CAR-T cell.
The activation scheme of the novel DN-T cell that the present invention creates, cytokine profiles and φt cell receptor combined stimulation scheme, can promote the transfection efficiency of Chimeric antigen receptor virus to greatest extent, improves the preparation efficiency of CAR-DN-T cell, with reference to shown in Fig. 3.
CAR-DN-T cell can derive from the CD3 of healthy human peripheral blood
+/ CD4
-/ CD8
-double negative t (DN T) cell, because healthy contributor's immunity system perfects, the activation of the CAR-DN-T cell of this kind of homology allosome, propagation and killing ability are all better than the CAR-T cell in autologous patient source, and tumor-killing ability is stronger, with reference to shown in Fig. 4, Fig. 5.
Embodiment
Anti-CD19CAR-DN-T (CAR-DN-T-19) cell is to the therapeutic action of CD19+B cell lymphoma mouse model.
CAR-DN-T-19 cell traditional C AR-T-19 cell is all prepared from same human peripheral lymphocytes.Utilize classical Lymphoma Mice modeling method, our end user CD19+Raji B cell system creates out mouse-human B cell lymphoma follow board.After CD19+Raji B cell injects 7 days, by mouse living imaging, clearly can observe this cell rapid amplifying in Mice Body, gather in a large number, modeling success is described.On the same day, successful for modeling mouse is divided into 3 groups by us, inject negative control T cell (Mock-T cells), CAR-T-19 and the CAR-DN-T cell of equal amts respectively, and this sky is defined as the 0th day (Day 0), the growing state of Raji cell in continuous observation Mice Body.The result display of living imaging, relative to negative control group, CAR-T-19 and CAR-DN-T-19 cell all can effectively suppress CD19+Raji B lymphoma cell grow, and is killed and wounded, removes, shown in reference Fig. 6.
Statistical result showed, CAR-T-19 and CAR-DN-T-19 cell all effectively can improve the survival rate of mouse, notable difference is not had between two groups, CAR-T-19 and CAR-DN-T-19 cell, illustrate that CAR-DN-T-19 cell has with the similar tumor-killing function of classical CAR-T-19 cell, with reference to shown in Fig. 7.
The foregoing is only the preferred embodiments of the present invention, be not limited to the present invention, for a person skilled in the art, the present invention can have various modifications and variations.Within the spirit and principles in the present invention all, any amendment done, equivalent replacement, improvement etc., all should be included within protection scope of the present invention.
Claims (3)
1. a construction process for Chimeric antigen receptor double negative t cells, is characterized in that: according to CD3
+/ CD4
-/ CD8
-the characteristic of double negative t cells, the external CD3 sub-electing purifying
+/ CD4
-/ CD8
-double negative t cells, utilize cytokine profiles signal path and the synergistic principle of TCR signal path, filter out the vitro culture scheme being suitable for double negative t cells activation and virus transfection, activation double negative t cells that can be quick, controlled, and specific Chimeric antigen receptor slow-virus transfection technique to high-efficiency rate is expressed on double negative t cells, prepare CAR-DN-T cell, can tumour cell corresponding to specific identification Chimeric antigen receptor, promote further activation and the propagation of CAR-DN-T cell, and quick killing tumor cell.
2. construction process according to claim 1, is characterized in that: described external sorting schemes is, utilizes the negative sorting of CD4/CD8 biotin labelled antibodies and CD3/CD28 marked by magnetic bead antibody positive sorting conbined usage, sub-elects highly purified CD3
+/ CD4
-/ CD8
-double negative t cells, then adds the cytokine mixed solution stimulation of specific proportioning mixing, cultivates and carry out Chimeric antigen receptor virus transfection after 72 hours, obtain a high proportion of CAR-DNT cell to the double negative t cells of purifying.
3. construction process according to claim 2, is characterized in that, described cytokine mixed solution comprises: IL-2, IL-15, GMCSF, TNF α, IFN γ.
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Cited By (9)
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|---|---|---|---|---|
| CN105647871A (en) * | 2016-01-27 | 2016-06-08 | 苏州佰通生物科技有限公司 | Chimeric antigen receptor T cell capable of conducting allograft and preparation method |
| CN106978442A (en) * | 2016-01-18 | 2017-07-25 | 爱康得生物医学技术（苏州）有限公司 | A kind of preparation method of Chimeric antigen receptor T cell |
| WO2017186121A1 (en) * | 2016-04-26 | 2017-11-02 | 科济生物医药（上海）有限公司 | Method for improving function of immune response cell |
| WO2021213235A1 (en) * | 2020-04-20 | 2021-10-28 | 浙江瑞加美生物科技有限公司 | Technique for preparing universal humanised car19-dnt cells and application therefor |
| CN114045309A (en) * | 2021-10-28 | 2022-02-15 | 郑州赛龙泰克生物科技有限公司 | Preparation method and application of universal chimeric antigen receptor regulatory T cells |
| CN114929865A (en) * | 2019-12-06 | 2022-08-19 | 大学健康网络 | Genetically engineered double negative T cells as adoptive cell therapy |
| WO2023078425A1 (en) * | 2021-11-05 | 2023-05-11 | 浙江瑞加美生物科技有限公司 | Method for efficiently and stably transducing antigen chimeric receptor double-negative t cells in vitro |
| WO2023125860A1 (en) * | 2021-12-30 | 2023-07-06 | 重庆精准生物技术有限公司 | Preparation technique for universal car-t cell, and application of universal car-t cell |
| EP4141105A4 (en) * | 2020-04-20 | 2024-05-29 | Ruichuang Biotech. Co., Ltd. | Universal-type efficient in-vitro amplification method for multiple times of clinical feedback of allogenic dnt cells |
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Cited By (13)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN106978442A (en) * | 2016-01-18 | 2017-07-25 | 爱康得生物医学技术（苏州）有限公司 | A kind of preparation method of Chimeric antigen receptor T cell |
| CN105647871A (en) * | 2016-01-27 | 2016-06-08 | 苏州佰通生物科技有限公司 | Chimeric antigen receptor T cell capable of conducting allograft and preparation method |
| WO2017186121A1 (en) * | 2016-04-26 | 2017-11-02 | 科济生物医药（上海）有限公司 | Method for improving function of immune response cell |
| CN108884459A (en) * | 2016-04-26 | 2018-11-23 | 科济生物医药（上海）有限公司 | A method of improving immune response cell function |
| CN108884459B (en) * | 2016-04-26 | 2024-04-02 | 科济生物医药（上海）有限公司 | Method for improving immune response cell function |
| CN114929865A (en) * | 2019-12-06 | 2022-08-19 | 大学健康网络 | Genetically engineered double negative T cells as adoptive cell therapy |
| EP4069831A4 (en) * | 2019-12-06 | 2024-02-28 | University Health Network | Genetically engineered double negative t cells as an adoptive cellular therapy |
| JP2023522112A (en) * | 2020-04-20 | 2023-05-26 | ジョージアン ルイジアメイ バイオテック カンパニー リミテッド | Technology for producing versatile humanized CAR19-DNT cells and use thereof |
| WO2021213235A1 (en) * | 2020-04-20 | 2021-10-28 | 浙江瑞加美生物科技有限公司 | Technique for preparing universal humanised car19-dnt cells and application therefor |
| EP4141105A4 (en) * | 2020-04-20 | 2024-05-29 | Ruichuang Biotech. Co., Ltd. | Universal-type efficient in-vitro amplification method for multiple times of clinical feedback of allogenic dnt cells |
| CN114045309A (en) * | 2021-10-28 | 2022-02-15 | 郑州赛龙泰克生物科技有限公司 | Preparation method and application of universal chimeric antigen receptor regulatory T cells |
| WO2023078425A1 (en) * | 2021-11-05 | 2023-05-11 | 浙江瑞加美生物科技有限公司 | Method for efficiently and stably transducing antigen chimeric receptor double-negative t cells in vitro |
| WO2023125860A1 (en) * | 2021-12-30 | 2023-07-06 | 重庆精准生物技术有限公司 | Preparation technique for universal car-t cell, and application of universal car-t cell |
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Application publication date: 20150722 |