Cancer combined treatment composition

A technology of combined therapy and composition, applied in the direction of drug combination, cancer antigen components, breast cancer vaccine, etc., can solve the problems of immunosuppressive microenvironment limitation, no therapeutic effect, no significant improvement of curative effect, etc., to achieve the solution of immune resistance Inhibit and reduce the inhibition of tumor microenvironment and improve the effect of anti-tumor immune response

Active Publication Date: 2021-11-19
XIAMEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, there are still many difficulties in the treatment of cancer, one of which is limited by the existence of the immunosuppressive microenvironment.
However, the current mainstream method of combining CAR-T therapy with PD-1 / PD-L1 blockade has not significantly improved the efficacy
CN105153315A discloses an immunosuppressive receptor combined with a cancer antigen chimeric receptor and its application. Cancer is recognized by a cancer antigen chimeric receptor, and a recombinant immunosuppressive receptor is combined with an immunosuppressive factor. However, its in vitro killing does not No significant improvement; CN107073138A discloses compositions and methods for reducing immune tolerance associated with CAR-T cell therapy, while expressing CAR and a modified PD-1, although effectively reducing PD-L1 The inhibition rate of CAR-T, but still did not show a good therapeutic effect; CN107325185A discloses a PSCA and PDL1 dual-targeting chimeric antigen receptor based on OCST-CAR, although it solves the problem of simultaneously expressing two sets of receptors The disadvantages of low efficiency and long cycle, but the in vitro killing rate of cancer cells is still not more than 60%
On the one hand, the therapeutic effects of the above patents are still limited; on the other hand, they usually only operate on the PD-1 / PD-L1 pathway. If other immune escape mechanisms are further inhibited, they will face the problems of difficult construction, complex design, and high cost. Therefore, it is urgently needed Propose a better combined treatment plan to solve the immunosuppression in CAR-T therapy and improve the anti-cancer effect of CAR-T

Method used

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  • Cancer combined treatment composition
  • Cancer combined treatment composition
  • Cancer combined treatment composition

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0063] This example is the preparation method of the CAR-T cells of the present invention.

[0064] (1) Packaging and preparation of lentivirus: Two days before transfection, 293T was mixed with 2.5×10 6 Spread on a 10cm plate and culture with 8mL complete medium DMEM+10%FBS. 2-4 hours before transfection, the 293T medium was replaced with 7 mL complete medium RMPI 1640+10% FBS. During transfection, 84 μL PEI was dissolved in 600 μL basal medium RMPI 1640 and allowed to stand for 2 min; then 42 μg plasmid was dissolved in 600 μL basal medium RPMI 1640, in which the EGFR-CAR recombinant transfer vector based on the pCDH vector (such as figure 1 As shown, see CN110845623A), the ratio of psPAX and pMD2G was 4:3:1, then PEI solution was added to the plasmid solution, shaken for 8 seconds immediately, and added to 293T cells after standing for 8 minutes. After 12 hours of transfection, the 293T medium was replaced with 12 mL of complete medium DMEM+10% FBS. After 60 hours of tra...

Embodiment 2

[0068] This example is for the screening of epigenetic regulators in combination therapy for different tumors.

[0069] The tumor cells cultured in vitro (triple-negative breast cancer cell MDA-MB-231 or brain glioma cell U87) were digested and placed in a 6-well plate for overnight culture. When the cell confluence reached 80% the next day, the culture was replaced. At the same time, add the CAR-T cells prepared in Example 1 (effect-to-target ratio E:T=1:2, use X-VIVO medium to suspend), and / or add different epigenetic regulators (250nM THZ1, 100 nM of JQ1, 20 μM of C646, 200 μM of MG149, 5 μM of KDM5-C70, 5 μM of ICDK9, dissolved in DMSO). After 48 hours of co-cultivation, remove the suspended CAR-T cells, use Eastep Super TotalRNA Extraction Kit (Promega) to extract the total RNA of tumor cells, and perform RT-qPCR detection; or after 72 hours of co-cultivation, remove the suspended CAR-T cells , tumor cells were lysed with RIPA lysate, the supernatant was obtained by ultr...

Embodiment 3

[0073] In this example, the combination of CAR-T and epigenetic regulators targeting CDK7 or BRD4 was tested on the transcriptional effects of various inhibitory immune checkpoints, inflammatory factors, immunosuppressive molecules and chemokines and other molecules related to immune escape. level down. Digest triple-negative breast cancer cells (MDA-MB-231 or MDA-MB468) and glioma cells (U87 or GBM-PDX) cultured in vitro, spread them in 6-well plates and culture overnight, and wait for the cells to reach confluence the next day When the degree reaches 80%, replace the medium and add the CAR-T cells prepared in Example 1 (effect-to-target ratio E:T=1:2, use X-VIVO medium to suspend), and / or add different apparent Genetic regulators: commonly used epigenetic regulators of CDK7 (250nM THZ1, 350nM THZ2, 1μM BS-181, 1μM CT7001) and BRD4 commonly used epigenetic regulators (100nM JQ1, 1μM IBET-151, Molibresib at 500 nM, Mivebresib at 500 nM, INCB057643 at 500 nM, Birabresib at 75 ...

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Abstract

The invention discloses a cancer combined treatment composition. The effective components comprise CAR-T cells and an epigenetic regulator, the CAR-T cells can recognize at least one cancer specific antigen or cancer related antigen; and the epigenetic regulator comprises at least one of a CDK7 inhibitor and a BRD4 inhibitor. Compared with a treatment mode of combining CAR-T with an inhibitor or an antibody for blocking a single immune escape pathway, the treatment mode of combining the CAR-T and the epigenetic regulator has a wider inhibition effect on a tumor microenvironment and is easier to operate and implement compared with other schemes for blocking multiple immune escape pathways in CAR-T treatment.

Description

technical field [0001] The invention belongs to the technical field of cancer treatment, and in particular relates to a combination treatment composition for cancer. Background technique [0002] Over the past few decades, immunotherapy has proven to be an effective approach in cancer treatment and has become an important part of many treatment regimens, offering new hope for better treatments. Immunotherapy is generally divided into two categories: "active" immunotherapy and "passive" immunotherapy. Among them, "active" immunotherapy is to enhance the activation of the immune system by regulating the endogenous immune mechanism (modulation and / or activation mechanism), including cancer vaccines. "Passive" immunotherapy uses effector cells / molecules of the immune system to directly attack cancer cells, including antibody-targeted therapy and its derivatives (such as antibody-drug conjugates), cytokine therapy, and adoptive immune cell therapy (such as Genetically engineere...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/06A61K39/00A61K31/506A61K31/551A61P35/00A61P35/04
CPCA61K45/06A61K39/0011A61K31/506A61K31/551A61P35/00A61P35/04A61K2039/812A61K2039/80A61K2039/545A61K2039/5158A61K2300/00
Inventor 刘文夏琳郑早早刘珺懿陈宇洁
Owner XIAMEN UNIV
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