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Method for immunotherapy prognosis of non-small cell lung cancer (NSCLC) patients

A technology for immunotherapy and patients, applied in biochemical equipment and methods, microbial measurement/testing, etc., can solve the problems of low proportion of MSI-H in tumors, inconsistent predictive ability of immunotherapy efficacy, difficulty in establishing consensus on TMB threshold, etc. To achieve the effect of improving patient benefit

Pending Publication Date: 2020-08-14
SHANGHAI ORIGIMED CO LTD
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Problems solved by technology

However, the results of multiple clinical trials have shown that the predictive ability of PD-L1 expression on the efficacy of immunotherapy is inconsistent, and some PD-L1-negative patients can still benefit from immunotherapy, and the duration of remission is not inferior to that of PD-L1-positive patients; TMB It is also an immunotherapy biomarker recommended by the NCCN guidelines for non-small cell lung cancer, but in view of the differences in TMB algorithms between different companies or laboratories, it is difficult to establish a consensus on the TMB threshold; MSI has been used as a key biomarker for tumors to allow FDA to agree based on MSI status rather than histopathological type , for drug treatment, but the proportion of MSI-H in the tumor is too low, and there are certain limitations in clinical promotion

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  • Method for immunotherapy prognosis of non-small cell lung cancer (NSCLC) patients
  • Method for immunotherapy prognosis of non-small cell lung cancer (NSCLC) patients
  • Method for immunotherapy prognosis of non-small cell lung cancer (NSCLC) patients

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Embodiment 1

[0032] To investigate the genetic characteristics of NFE2L2 and / or KEAP1 gene mutations in a Chinese NSCLC population. A total of 4637 Chinese NSCLC patients were collected, including 621 in LUSC and 4016 in LUAD. Next-generation sequencing of 450 cancer-related genes results in figure 1 As shown, NFE2L2 and / or KEAP1 mutations were highest in lung squamous cell carcinoma (LUSC) at 19.16% (NFE2L2) and 10.31% (KEAP1), respectively. Compared with previous reports, NFE2L2 (0.89%) and KEAP1 (3.74%) were mutated at lower frequencies in lung adenocarcinoma (LUAD). We observed an amplification frequency of NFE2L2 in the entire cancer database as high as 19.2% (80 out of 417), suggesting that the NRF2 pathway is activated in cancer. Among them, the amplification frequency of NFE2L2 in non-small cell lung cancer was 19.1% (33 out of 173). In addition, we analyzed the distribution of somatic mutations on the NFE2L2 and KEAP1 protein schematics. Consistent with previous reports, mutat...

Embodiment 2

[0034] TMB values ​​obtained by the NGS algorithm, counts include the total number of somatic mutations encoding SNVs and short indels. Driver mutations and known germline rotations in the dbSNP database were not calculated. TMB was calculated by dividing the total number of mutations counted by the size of the coding region. The result is as figure 2 shown, in LUSC and LUAD, NFE2L2 and / or KEAP1 mutations were significantly associated with higher TMB values, although the two genes had different mutation frequencies.

Embodiment 3

[0036] To determine whether NFE2L2 and / or KEAP1 mutations increase PD-L1 expression, the correlation of LUSC, LUAD was assessed using PD-L1 immunohistochemical staining in NSCLC patients. PD-L1 expression status can be estimated by IHC staining of FFPE tissue sections with anti-PD-L1 antibodies (clone 28-8; Cat#ab205921; Abcam or clone 22C3; Cat#M3653; Dako). Abcam Universal HIER Antigen Recovery Reagent is used for antigen recovery. Nonspecific binding was blocked with DakoEnVision FLEX peroxidase blocking reagent. Other staining was mainly performed with Dako series reagents (Cat#K8002; Dako). A sample was considered positive for PD-L1 if the percentage of stained cells was ≥1%. The results showed that NFE2L2 mutation was associated with increased PD-L1 expression in LUSC, see image 3 A. In contrast, no clear association was observed in the KEAP1 mutant subset. The opposite is true for LUAD, see image 3 B, Only KEAP1 mutations are associated with increased PD-L1 expr...

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Abstract

The invention belongs to the technical field of immunotherapy prognosis, and in particular relates to a method for immunotherapy prognosis of non-small cell lung cancer (NSCLC) patients. The method uses a gene NFE2L2 and / or KEAP1 as a biomarker, whether the biomarker is mutated or not is detected, and thereby the prognosis of the sensitivity of NSCLC patients to immunotherapy, especially immunotherapy with immune checkpoint inhibitors (ICIs) is performed. In addition, the invention also provides a kit including biomarker detection reagents and an application of the kit. The method or the kit of the invention can be used to accurately predict the population sensitive to ICIs immunotherapy among NSCLC patients with NFE2L2 and / or KEAP1 mutations, and thereby the effectiveness and clinical benefit of immunotherapy for such patients are improved.

Description

technical field [0001] The invention belongs to the technical field of treatment and prognosis of non-small cell lung cancer, and particularly relates to a method for the prognosis of non-small cell lung cancer (NSCLC) patients by immunotherapy. Background technique [0002] NFE2L2 (nuclear factor erythroid-2-related factor-2, encoding NRF2) is a key transcription factor in cellular antioxidant response. At steady state, KEAP1 interacts with the DLG and ETGE motifs of NRF2 through its kelch domain and negatively regulates NRF2 through the KEAP1-CUL3-RBX1 E3 ubiquitin ligase complex. Many studies have revealed that the KEAP1-NRF2 system is a "double-edged sword" in the prevention and promotion of tumors during tumorigenesis. Activation of NRF2 in non-transformed cells prevents oxidative stress-induced carcinogenesis. In contrast, emerging evidence suggests that NRF2 activation in cancer cells promotes cancer progression and metastasis, and more importantly, leads to chemo / r...

Claims

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Application Information

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IPC IPC(8): C12Q1/6886
CPCC12Q1/6886C12Q2600/156C12Q2600/106C12Q2600/118
Inventor 王凯邢宇彤
Owner SHANGHAI ORIGIMED CO LTD
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