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Combined Drug Combinations for Tumor Immunotherapy

An immunotherapy and tumor technology, which is applied in the field of combined drug therapy of tumor immunotherapy, can solve the problems of undisclosed association and achieve the effect of an effective treatment plan

Active Publication Date: 2020-06-19
CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, the prior art does not disclose the association between ACAT1 and tumor immunotherapy

Method used

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  • Combined Drug Combinations for Tumor Immunotherapy
  • Combined Drug Combinations for Tumor Immunotherapy
  • Combined Drug Combinations for Tumor Immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1A

[0204] Example 1 ACAT1 gene knockout does not trigger CD8 T cells to respond to self-antigens and autoimmunity

[0205] The purpose of this example is to study whether the enhanced effector function of CD8 T cells after removing the function of ACAT1 will make CD8 T cells respond to self-antigens and induce autoimmune diseases. To study this, the Acat1 CKO The mice were further mated with OT-I TCR transgenic mice (Jax mice) to obtain ACAT1-specific knockout mice (OT-I Acat1 CKO ) and corresponding control mice (OT-I). The vast majority of T cells in OT-I transgenic mice are OT-I CD8 T cells, whose TCR specifically recognizes H2K b Presented Ovalbumin (OVA 257-264 ) antigen (N4 for short), and generate the corresponding CD8 T cell immune response; at the same time, OT-I TCR can also recognize a series of OVA mutants (A2, T4, G4, R4) in addition to its wild-type antigen (N4). ), and generate a corresponding strong or weak immune response. Experiments have found that ACAT1 d...

Embodiment 2

[0206] Example 2 Using Three Melanoma Models to Study ACAT1 Gene Knockout Promotes the Anti-tumor Activity of CD8 T Cells

[0207] Immunotherapy is currently a hot spot in the treatment of tumors, and the ability of CD8 T cells to kill tumor cells is directly related to the effect of tumor immunotherapy. In order to verify the effect of ACAT1 knockout on the anti-tumor ability of CD8 T cells, this example first established a subcutaneous melanoma model, in which Acat1 CKO Melanoma induced by subcutaneous injection of B16F10 melanoma cells in mice and wild-type mice, Acat1 CKO The progression of melanoma in mice was significantly delayed, as demonstrated by slower tumor growth and longer survival and survival in mice ( figure 2 .a,b). The phenotype of T cells in tumor-bearing mice was analyzed, and it was found that Acat1 CKO In mice, tumor-infiltrating CD8 T cells were more active and expressed Acat1 CKO In tumor-infiltrating CD8 T cells in mice, there are more effector c...

Embodiment 3

[0211] Example 3 ACAT inhibitor Avasimibe enhances the anti-tumor function of CD8 T cells

[0212] The purpose of this example is to further verify the application of ACAT1 inhibitors in tumor immunotherapy. ACAT1 is used as a target for the treatment of atherosclerosis, and a series of small molecule drugs are currently undergoing animal and clinical trials. Avasimibe is one of them, and many clinical trials have verified the safety of Avasimibe. Therefore, Avasimibe was selected to verify the possibility of ACAT1 as a target for tumor immunotherapy. In vitro experiments showed that Avasimibe, like other ACAT inhibitors such as CP113, 818 and K604, could promote the release of granzyme B and the expression of cytokines IFNγ and TNFα in CD8 T cells ( image 3 .a). The in vitro killing experiment also showed that Avasimibe enhanced the target cell killing ability of CTL, and showed a dose effect ( image 3 .b). The experiment further verified the effect of Avasimibe in the...

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Abstract

The invention provides a drug combination for tumor immunotherapy, which includes an effective amount of an acyl-CoA:cholesterol acyl transferase ACAT1 inhibitor and an effective amount of an immune checkpoint blocking antibody. The present invention further provides a combination drug method for tumor immunotherapy. The present invention finds that inhibiting acyl-CoA:cholesterol acyltransferase ACAT1 can enhance the tumor-killing activity of CD8 T cells, and in combination with immune checkpoint blocking antibodies, the two can have a synergistic effect, and can further enhance the anti-tumor activity. inhibition.

Description

technical field [0001] The invention belongs to the field of biotechnology, and in particular relates to combined medicine for tumor immunotherapy. Background technique [0002] Malignant tumors are currently one of the most lethal diseases. Conventional treatment methods such as surgical resection, radiotherapy and chemotherapy are widely used in tumor treatment. However, these methods have limitations in the treatment of tumors, and it is difficult to completely cure them. Tumors, especially some metastatic malignant tumors. [0003] Immunotherapy has always been a research hotspot in tumor treatment. Cytokines interleukin-2 (IL2) and interferon-α (IFNα) have been used in the treatment of renal cell carcinoma and melanoma for more than two decades, although the target specificity is weak and the toxicity is high. In recent years, with anti-PD-1 (programmed death 1) and anti-CTLA-4 (cytotoxic T [0004] Lymphocyte-associated antigen-4) and other immune checkpoint blockin...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): A61K45/00A61K45/06A61K39/395A61P35/00A61P35/02
CPCA61K39/39566A61K45/00A61K45/06A61K2039/542A61K2300/00A61K39/395A61K39/3955C07K16/2818A61K2039/505C07K2317/76A61K31/18A61K31/655A61P35/00A61K31/44A61K39/39558
Inventor 许琛琦李伯良杨魏白轶冰熊缨
Owner CENT FOR EXCELLENCE IN MOLECULAR CELL SCI CHINESE ACAD OF SCI
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