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Biomarker for judging efficacy of immune checkpoint inhibitor

A technology of immune checkpoints and substances, applied in the field of treatment of malignant tumors

Pending Publication Date: 2021-01-08
ONO PHARMA CO LTD +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] So far, it has been reported that CD8 in peripheral blood + The ratio between the number of T cells and the number of Treg cells may be related to the prognosis of patients with malignant tumors (Non-Patent Document 1), but there is no report on the following therapy: Combination of respective PD-1 expression intensity, PD-1 expression percentage, etc., to predict the presence or absence of effectiveness of immune checkpoint inhibitors prior to administration, and then prescribe immune checkpoint inhibitors to patients based on this biomarker agent

Method used

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  • Biomarker for judging efficacy of immune checkpoint inhibitor
  • Biomarker for judging efficacy of immune checkpoint inhibitor
  • Biomarker for judging efficacy of immune checkpoint inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0430] Example 1: Collection of Lymphocytes from Tumor Tissue and Identification of T Cells by Flow Cytometry

[0431] Tumor tissue was collected from cancer patients prior to administration of nivolumab, and tumor infiltrating lymphocytes were isolated by disrupting the tissue with a gentleMACSDissociator (MiltenyiBiotec). Peripheral blood mononuclear cells were prepared by density gradient centrifugation using Ficoll from the peripheral blood of the same patients prior to administration of substances that inhibit immune checkpoints. The isolated tumor-infiltrating lymphocytes and peripheral blood mononuclear cells were suspended in PBS (hereinafter referred to as "FACS buffer") added so that the final concentration of fetal calf serum was 2%, and human Fc Receptor binding inhibitor (ThermoFisher), and the mixture was stored at 4°C for 10 minutes. Thereafter, fluorescently-labeled antibodies against various cell surface markers (CD3, CD8, CD4, CD45RA, and PD-1) were added ...

Embodiment 2

[0433] Example 2: Based on Treg cells and CD8 + The respective PD-1 expression intensity in T cells, assessed for the determination of NiV Biomarkers of mAb effectiveness (non-small cell lung cancer)

[0434] Treg cells, Treg cells (Fr. + The expression intensity of PD-1 in T cells, and calculate its mean fluorescence intensity (MFI).

[0435] Among patients with non-small cell lung cancer, 7 patients showed the effect of CR or PR and 7 patients showed SD or PD by nivolumab administration. One remaining patient could not be evaluated and was therefore excluded from the following evaluations.

[0436] figure 1 and 2 The calculated values ​​for each of the patient group showing CR or PR (hereinafter referred to as "CR / PR group") and the patient group showing SD or PD (hereinafter referred to as "SD / PD group") are shown. + The respective results of the ratio of PD-1 expression MFI in T cells to Treg cells and PD-1 expression MFI in Treg cells (Fr.II). In addition, th...

Embodiment 3

[0441] Example 3: Based on Treg cells and CD8 + The respective PD-1 expression intensity in T cells, assessed for the determination of NiV Biomarkers of mAb effectiveness (gastric cancer)

[0442] Treg cells, Treg cells (Fr.II) and CD8 were measured by flow cytometry in tumor tissues derived from 17 patients with gastric cancer + The expression intensity of PD-1 in T cells and calculate its MFI.

[0443] Among patients with gastric cancer, 3 patients showed an effect of PR and 14 patients showed SD or PD by the administration of nivolumab.

[0444] image 3 and 4 Shows the relative CD8 calculated in the group of patients showing PR and the "SD / PD group + The respective results of the ratio of PD-1 expression MFI in T cells to Treg cells and PD-1 expression MFI in Treg cells (Fr.II). In addition, the upper and lower bounds of the 95% confidence intervals were calculated based on the means and standard deviations of the same ratios in each group. Table 2 shows the r...

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Abstract

The present invention addresses the problem of providing: a method for identifying a malignant tumor patient in whom an immune checkpoint inhibitor can be expected to be more effective; and an agent for suppressing the advance, suppressing the recurrence, and / or treating a malignant tumor characterized by prescription based on the method. The present invention provides: the determination of a malignant tumor patient in whom an immune checkpoint inhibitor can be expected to be more effective, said determination being made by analyzing evaluation items comprising a combination of PD-1 expressionintensity and proportion of PD-1 expressing cells, etc., in Treg cells and CD8+ T cells in tumor tissue or blood; and an agent for suppressing the advance, suppressing the recurrence, and / or treatinga malignant tumor characterized by prescription based on the determination.

Description

technical field [0001] The present invention relates to methods for identifying patients with malignancies on whom the effects of immune checkpoint inhibitors can be more expected, and methods for inhibiting the progression of malignancies, inhibiting the recurrence of malignancies and / or treating malignancies, It is characterized by a prescription based on the method described above. Background technique [0002] Unlike conventional therapies such as surgery, radiation therapy, and drug therapy with antineoplastic or molecularly targeted agents, cancer immunotherapy acts on immune surveillance mechanisms inherent in patients with malignancy. This is a therapy that suppresses or treats the progression of a malignancy by boosting immunity against the malignancy. Recent studies on tumor immunity have shown that the development of malignancy involves an immunosuppressive environment centered on its local tumor tissue, and that the tumor itself employs systems to evade mechanis...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K45/00A61K39/395A61P35/00A61P35/02A61P43/00G01N33/48G01N33/53
CPCG01N33/6872G01N15/14C12Q1/6886G01N2333/70521G01N2800/52C12Q2600/158C12Q2600/136G01N33/53G01N33/574G01N33/505G01N2333/70514G01N2333/70596A61K39/395A61K45/00A61P35/00A61P35/02A61P43/00G01N33/48G01N33/483G01N33/57492A61K2039/507C07K16/2818
Inventor 西川博嘉富樫庸介大山行也吉田隆雄竹田和彦幸田健一本田淳大八木笃柿沼桃瑠村田昌行
Owner ONO PHARMA CO LTD