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Compositions and methods for characterizing solid tumors responsiveness to Anti-pd-l1 antibody monotherapy

A technology for PD-L1 and solid tumors, applied in chemical instruments and methods, antibodies, drug combinations, etc.

Inactive Publication Date: 2019-07-02
免疫医疗有限责任公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0006] Despite remarkable progress over the past decade in developing strategies to combat cancer and other diseases, patients with advanced, refractory, and metastatic disease have limited clinical options

Method used

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  • Compositions and methods for characterizing solid tumors responsiveness to Anti-pd-l1 antibody monotherapy
  • Compositions and methods for characterizing solid tumors responsiveness to Anti-pd-l1 antibody monotherapy
  • Compositions and methods for characterizing solid tumors responsiveness to Anti-pd-l1 antibody monotherapy

Examples

Experimental program
Comparison scheme
Effect test

example 1

[0110] Example 1: CXCL9, CD274, LAG3, and IFNG are associated with objective response rate (ORR) in NSCLC

[0111] The safety and clinical activity of durvalumab in advanced solid tumors was evaluated. RNA sequencing data were generated on patient tumors with available clinical data, of which 30 had pre / post NSCLC patient tumor pairs and 30 bladder patient tumors were pretreated with available clinical data and subjected to bioinformatics analysis. The following genes were assessed: CXCL9, PD-L1(CD274), LAG-3, IFNG, PD-1(PDCD1), NKG7, CD8A, SLAMF7, PD-L2(PDCD1LG2), TIM-3(HAVCR2), CD80, CD86 , CTLA-4, CD2, TLR8, GZMK, TNFRSF4, FOXP3, CD276, B7-H4 (VTCN1 ), and CD37.

[0112] Of the 21 candidate genes evaluated, each gene was segmented into a low or high group using receiver operating characteristic (ROC) calculations using area under the curve (AUC), logistic regression, time-to-event analysis such as Kaplan- The calculations were performed with Mayer and Cox proportional haz...

example 2

[0118] Example 2: CXCL9, CD274, LAG3 and IFNG are associated with overall response (OS) or progression-free response (PFS) in NSCLC

[0119] Patients were divided into high or low expression groups using the same cutpoints for each of the top four genes identified from the ORR analysis (CXCL9, CD274, LAG3, and IFNG). Kaplan-Meier estimates (KM) analyzes were then performed using overall response (OS) or progression-free response (PFS) as endpoints for each gene individually ( Figures 1A-1H ). Figures 1A-1D Panels showing overall responses to CXCL9, IFNG, LAG3 and CD274 (PDL1 ) in NSCLC patients. Each panel was segmented into high or low expression using cutpoints identified by ROC. Figures 1E-1H Panels showing progression-free survival for CXCL9, IFNG, LAG3 and CD274 (PDL1) in NSCLC patients. Each panel was segmented into high or low expression using cutpoints identified by ROC.

[0120] Using the log-rank test, all four genes showed statistical differences between the h...

example 3

[0121] Example 3: CD274(PDL1) did not show significant induction after treatment

[0122] Significant induction of each of the four genes (CXCL9, CD274, LAG3 and IFNG) following treatment with durvalumab was assessed. Paired t-tests were calculated between post-treatment and pre-treatment time points for each gene individually. The results are reported in Table 3. Only CD274 (PDL1 ) showed no significant induction at α=0.05 after treatment. These results indicated that three of the four genes were induced in tumors by durvalumab, suggesting immune activation of relevant immune-specific genes caused by treatment with this molecule.

[0123] Table 3. The therapeutic effect of durvalumab on four genes in NSCLC

[0124]

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Abstract

The present invention provides methods for selecting patients as having a solid tumor (e.g., bladder cancer, ovarian cancer, colorectal cancer, head and neck cancer, cervical cancer, renal cell carcinoma, and non-small cell lung cancer (NSCLC)) that is responsive to treatment with an anti-PD-L1 antibody, and methods of treating such patients. The method involves detecting expression of an IFNG polynucleotide and / or one or more of polynucleotide markers: CXCL9, CD274, and LAG3, in a biological sample of the patient.

Description

Background technique [0001] Cancer remains a major global health burden. Despite advances in the treatment of cancer, there remains an unmet medical need for more effective and less toxic therapies, especially for those patients with advanced disease or cancer that is resistant to existing treatments . [0002] Lung cancer is one of the most common forms of cancer and the leading cause of cancer death in both men and women. Lung cancer kills more people each year than colon, breast and prostate cancer combined. Non-small cell lung cancer is the most common form of lung cancer. Although patients with a history of smoking have a higher risk of developing lung cancer, lung cancer can also affect non-smokers. Despite improvements in medical treatments, improving the survival rate of lung cancer patients remains difficult. Most lung cancers are only detected at an advanced stage when treatment options are limited. It is increasingly recognized that lung cancer and other malig...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): A61K31/7088A61P35/00C12N15/113
CPCA61K2039/505A61P35/00C07K16/2827C07K2317/21C07K2317/76
Inventor B.W.希格斯C.摩尔豪斯P.布罗豪恩K.施特莱彻K.拉纳德
Owner 免疫医疗有限责任公司
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