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Method for predicting sensitivity of patients with NSCLC (non-small cell lung cancer) to immunotherapies

A technology for non-small cell lung cancer and immunotherapy, applied in biochemical equipment and methods, microbial determination/inspection, instruments, etc., can solve problems such as restricting clinical application, long working cycle, and high technical platform requirements.

Active Publication Date: 2019-10-08
SHANGHAI ORIGIMED CO LTD
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  • Description
  • Claims
  • Application Information

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Problems solved by technology

However, since different anti-PD-(L)1 drugs have their own corresponding PD-(L)1 detection antibodies and platforms, there is a lack of uniform standards for PD-L1 detection; in addition, the expression of PD-L1 has the characteristics of dynamic changes. The relationship between PD-L1 expression and the effect of immunotherapy is still controversial; on the other hand, although a large number of randomized controlled studies and large-sample real-world studies have confirmed the correlation between TMB and immunotherapy, TMB is still only It can reflect the number of tumor mutations, but not the state of the tumor microenvironment, and TMB detection has high requirements on the technical platform, long working cycle, and high cost, which restrict its clinical application

Method used

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  • Method for predicting sensitivity of patients with NSCLC (non-small cell lung cancer) to immunotherapies
  • Method for predicting sensitivity of patients with NSCLC (non-small cell lung cancer) to immunotherapies
  • Method for predicting sensitivity of patients with NSCLC (non-small cell lung cancer) to immunotherapies

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Embodiment 1

[0088] genome analysis

[0089] FFPE tumor samples from Chinese non-small cell lung cancer (NSCLC) patients and paired peripheral whole blood control samples were studied. All patients provided written informed consent. Target-captured next-generation sequencing (NGS) at OrigiMed involves panels containing 450 cancer-related genes. DNA was extracted from all unstained FFPE sections and whole blood with no less than 20% tumor content by DNA FFPE Tissue Kit and DNA Mini Kit (QIAamp), and then quantified by dsDNA HS Assay Kit (Qubit). Using KAPA Hyper Prep Kit (KAPA Biosystems), the sonicated DNA of about 250 bp was fragmented to construct a library, followed by PCR amplification and quantification. Hybrid capture using a custom panel covering 2.6Mb of the human genome, targeting 450 cancer-associated genes and certain frequently rearranged introns. The captured libraries were pooled, denatured, and diluted to 1.5-1.8 pM, followed by paired-end sequencing on an Illumina NextSe...

Embodiment 2

[0106] A total of 637 patients with non-small cell lung cancer (NSCLC) participated in the study. The characteristics of the patients are shown in Table 1. Most patients were male (355 / 637, 55.7%), and the median age at diagnosis was 60 years (IQR, 53-67 years). The most common histological type was non-squamous cell carcinoma (N=553, 86.8%), including adenocarcinoma (N=537) and other non-squamous cell carcinoma (N=16). Among them, there were 211 cases (33.1%) in stage I, 64 cases (10%) in stage II, 138 cases (21.7%) in stage III, and 224 cases (35.2%) in stage IV. 637 patients were tested for PD-L1 and TMB. The distribution of PD-L1 expression and TMB according to demographic characteristics is shown in Table 1. Weak positive (PD-L1 TPS score = 1-49%) and strong positive PD-L1 expression (PD-L1 TPS score ≥ 50%) were 16.5% and 10%, respectively. We performed a univariate analysis of the association between PD-L1 expression (assessed as a categorical variable with cutoffs o...

Embodiment 3

[0109] The top three mutated genes in the cohort of 637 NSCLC patients were TP53 (55.9%), EGFR (51.3%) and KRAS (12.6%). Among 637 NSCLC patients, 32 patients carried KMT2C gene mutation, accounting for 5%. Among the 32 patients with KMT2C mutation, 24 patients also carried TP53 gene mutation, accounting for 75%. The TMB of KMT2C mutant patients was significantly higher than that of KMT2C wild-type patients (median TMB: 13.1 vs. 4.6, pfigure 1 ). The positive expression rate of PD-L1 in patients with KMT2C mutation (PD-L1TPS≥1%) was higher than that in KMT2C wild-type patients (34.4% vs. 26.1%, p>0.05) ( figure 2 ).

[0110] In the cohort of 637 NSCLC patients, 42.9% (273 / 637) were TP53-WT / KMT2C-WT patients, 1.3% (8 / 637) were TP53-WT / KMT2C-MUT patients, and 52.1% (332 / 637) were TP53 -MUT / KMT2C-WT patients, 3.7% (24 / 637) were TP53-MUT / KMT2C-MUT patients. The tumor TMB of TP53-WT / KMT2C-MUT patients was significantly higher than that of TP53-WT / KMT2C-WT patients (median TMB:...

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Abstract

The invention discloses a method for predicting sensitivity of patients with a cancer (non-small cell lung cancer) to immunotherapies, such as immunotherapy using an immune checkpoint inhibitor, by using KMT2C and TP53 genes as biomarkers, and also discloses application of a reagent, which detects the biomarkers specifically, in the preparation of kits to predict the sensitivity of patients with acancer (non-small cell lung cancer) to immunotherapies, such as immunotherapy using an immune checkpoint inhibitor. Through the combinatory consideration of TP53 and KMT2C gene mutation states herein, groups sensitive to ICIs (immune checkpoint inhibitors) can be predicted accurately from patients with NSCLC (non-small cell lung cancer), blind medication is avoided, and economy of ICI therapy isimproved.

Description

technical field [0001] The invention relates to the field of biomedicine. In particular, the present invention relates to a method, kit and system for predicting the sensitivity of non-small cell lung cancer (NSCLC) patients to immunotherapy, eg, immunotherapy using immune checkpoint inhibitors. More specifically, the present invention relates to the use of the KMT2C gene and the TP53 gene as biomarkers to predict the sensitivity of cancer patients to immunotherapy, such as immunotherapy using immune checkpoint inhibitors. Background technique [0002] Clinically, lung cancer is divided into two types: small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). This distinction is important because the treatment options for these two types of lung cancer are quite different. Differentiating between the two types requires bronchoscopy, biopsy or postoperative pathology, which can only be determined after a pathologist's diagnosis. Compared with small cell lung ...

Claims

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Application Information

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IPC IPC(8): C12Q1/6886G16B20/50
CPCC12Q1/6886C12Q2600/106C12Q2600/156G16B20/50
Inventor 张史钺王文静张琳王凯
Owner SHANGHAI ORIGIMED CO LTD
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