Stromal gene signatures for diagnosis and use in immunotherapy

A technology of immunotherapy and matrix, applied in the direction of disease diagnosis, immunoglobulin, chemical instruments and methods, etc., which can solve the problems of not experiencing therapeutic benefits

Active Publication Date: 2019-02-05
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, many patients do not experience therapeutic benefit, possibly due to the presence of other immunosuppressive mechanisms in the TME

Method used

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  • Stromal gene signatures for diagnosis and use in immunotherapy
  • Stromal gene signatures for diagnosis and use in immunotherapy
  • Stromal gene signatures for diagnosis and use in immunotherapy

Examples

Experimental program
Comparison scheme
Effect test

Embodiment approach

[0338] The present invention provides following embodiment:

[0339] 1. A method for treating an individual with a disease or condition, the method comprising:

[0340] a) determining the presence of a matrix gene signature comprising one or more of FAP, FN1, MMP2, PDGFRB, or THY1 in a sample from the individual, wherein the matrix gene signature is one or more of the genes An increase in the expression level relative to the median level identifies a treated individual; and

[0341] b) administering to said individual an effective amount of immunotherapy and an inhibitory stroma antagonist.

[0342] 2. A method for improving immunotherapy in an individual with a disease or condition, the method comprising:

[0343] a) determining the presence of a matrix gene signature comprising one or more of FAP, FN1, MMP2, PDGFRB, or THY1 in a sample from the individual, wherein the matrix gene signature is one or more of the genes An increase in the expression level relative to the med...

Embodiment 1

[0508] Example 1: Tumor-infiltrating stromal gene signatures across urothelial carcinoma (UC) and their association with resistance to anti-PD-L1 antibody therapy

[0509] foreword

[0510] To assess and understand the complexity of factors that may regulate or suppress antitumor immunity and thus contribute to resistance to immunomodulatory therapies, a highly sensitive immune gene expression assay was implemented to investigate Tumor microenvironment (TME) of tumor tissue before treatment.

[0511] Materials and methods

[0512] The Illumina TruSeq RNA Access RNA-seq kit was implemented to investigate the tumor microenvironment (TME) in pre-treatment tumor tissues from urothelial carcinoma patients (n=217). Illumina TruSeq RNA Access RNA-seq captures and investigates genes across the entire human genome (>20,000 genes).

[0513] RNA was extracted from formalin-fixed, paraffin-embedded archived tissue. Tumor tissue was collected clinically from the Phase II IMvigor210 stu...

Embodiment 2

[0521] Example 2: Tumor stromal signatures across five cancer types and their association with disease prognostic factors Introduction

[0522] To further assess and understand the complexity of factors that may regulate or suppress antitumor immunity and thus contribute to response or resistance to immunomodulatory therapies, a highly sensitive immune gene expression assay was implemented to investigate (BC), tumor microenvironment (TME) of pretreatment tumor tissues of lung cancer, melanoma, RCC, and bladder cancer.

[0523] Materials and methods

[0524] Implementation of the Illumina TruSeq RNAAccess RNA-seq kit to investigate tumors from BC (n=73), lung (n=59), melanoma (n=34), RCC (n=55), and bladder cancer (n=44) The tumor microenvironment (TME) of the patient's tumor tissue before treatment. Illumina TruSeq RNAAccess RNA-seq captures and investigates genes across the entire human genome (>20,000 genes).

[0525] RNA was extracted from formalin-fixed, paraffin-embedd...

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Abstract

The invention provides methods for identifying an individuals with a disease or disorder who is less likely to respond to immunotherapy alone, the method comprising determining the presence of a stromal gene signature in a sample from the individual, said signature comprising one or more of FAP, FN1, MMP2, PDGFRB, or THY, wherein an increase in the level of expression of the one or more genes in the stroma gene signature relative to a median level identifies an individual for treatment with an immunotherapy and with a suppressive stromal antagonist. In some aspects, the invention provides methods for treating an individual displaying the stromal gene signature. In other aspects, the invention provides kits for determining the presence of a stroma gene signature in a sample from an individual.

Description

[0001] Cross references to related applications [0002] This application claims the benefit of U.S. Provisional Application 62 / 337,815, filed May 17, 2016, the contents of which are hereby incorporated by reference in their entirety. field of invention [0003] The present invention provides tumor stromal biomarkers and methods for selecting and treating cancer patients with immunotherapy in combination with an inhibitory stromal antagonist. Background of the invention [0004] As tumors grow in tissues, they form a tumor microenvironment (TME), which contains non-malignant cells, including blood endothelial cells (BECs) and lymphoid endothelial cells (LECs), mesenchymal stem cells (MSCs) and their differentiated progeny , a complex mixture of cancer-associated fibroblasts (CAFs), pericytes, and immune cells, together with their secreted extracellular matrix (ECM) and inflammatory mediators (Turley, S.J. et al., Nature Reviews Immunology, 15:669 -682, 2015). Both healthy ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6886
CPCC12Q1/6886C12Q2600/106C12Q2600/118C12Q2600/158A61P35/00G01N33/574G01N2800/52G01N2333/71G01N2333/78G01N2333/705G01N2333/96433C07K16/2827C07K16/2866C07K2317/24C07K2317/32C07K2317/75G01N33/57415G01N33/5743G01N33/57492
Inventor P·海格L·莫里诺S·马里亚萨桑S·特利J·阿斯塔里塔R·古巴斯Y·杨
Owner F HOFFMANN LA ROCHE & CO AG
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