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Diagnostic and therapeutic methods for cancer

A therapy and cancer technology, applied in the field of cancer diagnosis and treatment, can solve the problems of suppressing anti-tumor immune activity and down-regulating T cell activation

Pending Publication Date: 2020-05-29
F HOFFMANN LA ROCHE & CO AG
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Formation of PD-L1 / PD-1 and PD-L1 / B7-1 complexes negatively regulates T cell receptor signaling, leading to subsequent downregulation of T cell activation and suppression of antitumor immune activity

Method used

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  • Diagnostic and therapeutic methods for cancer
  • Diagnostic and therapeutic methods for cancer
  • Diagnostic and therapeutic methods for cancer

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0765] Example 1: Pre-existing tumor immunity is associated with a complete response in inflamed tumors

[0766] Most human solid tumors appear to exhibit one of three distinct immune phenotypes: an "immuno-inflamed" phenotype, characterized by robust CD8+ T cell infiltration and PD-L1 expression; an "immuno-excluded" phenotype, in which T cells Accumulation in extracellular matrix-rich stroma; and "immune desert" phenotype, which is characterized by a depletion of infiltrating lymphocytes in the tumor or surrounding stroma. Inflamed tumors are thought to be more responsive to checkpoint blockade compared to immune-depleted or immune-desert phenotypes that predict weak or no responsiveness. However, this association has not been systematically tested in the context of large clinical trials or within a single tumor type. To understand the response to atezolizumab therapy in mUC, we combined an integrated molecular and histological analysis with a reverse translation approach t...

Embodiment 2

[0774] Example 2: Tumor mutational burden (TMB) driven by proliferation, APOBEC expression, or DNA damage repair deficiency is associated with response to atezolizumab

[0775] Along with melanoma and non-small cell lung cancer, bladder cancer is characterized by one of the highest somatic TMB among human cancers. Response to atezolizumab was significantly associated with TMB in mUC, and this association was also significant in the full IMvigor210 dataset ( Figure 1E ). The correlation of TMB is likely via the elevated potential of immunogenic neoantigens, and consistent with this, predicted tumor neoantigen burden (TNB) was also significantly associated with response ( Figure 1F ). TMB and TNB are also related to OS ( Figure 1V and 1W ). For example, using the median TMB as a cutoff, an improved OS benefit from atezolizumab was observed in patients with high TMB relative to patients with low TMB ( Figure 8B ). Improved OS from atezolizumab was also observed in pati...

Embodiment 3

[0796] Example 3: The TGF-β axis is associated with major immune escape

[0797] Next, we sought to identify any additional features associated with the response beyond CD8+ T cell immunity and TMB. Consistent with the positive correlation between proliferation and TMB, gene sets related to DNA replication, cell cycle, and histones were significantly enriched in responders ( Figure 1O , Table 8). Gene set enrichment analysis also identified the cytokine-cytokine receptor gene set as the only signature associated with non-response ( Figure 1O , Table 8). Importantly, the most significantly associated genes within this pathway were IFNGR1 and genes involved in the TGF-β signaling pathway, including TGFB1, ACVR1, and TGFBR2. Although IFN-γ is known to have beneficial effects on antitumor immunity, this cytokine has also emerged as a key player in primary resistance to checkpoint therapy and in acquired immune escape. In our large cohort of patients with mUC, we observed sig...

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Abstract

The present invention provides diagnostic methods, therapeutic methods, and compositions for the treatment of cancer (e.g., a bladder cancer (e.g., UC, e.g., mUC), a kidney cancer, a lung cancer, a liver cancer, an ovarian cancer, a pancreatic cancer, a colorectal cancer, or a breast cancer). The invention is based, at least in part, on the discovery that expression levels of one or more biomarkers described herein in a sample from an individual having cancer can be used in methods of identifying an individual having a cancer who may benefit with an anti-cancer therapy that includes an immunotherapy (e.g., a PD-L1 axis binding antagonist such as an anti-PD-L1 antibody (e.g., atezolizumab)) and a suppressive stromal antagonist (e.g., a TGF-beta antagonist), methods for selecting a therapy for an individual having cancer, methods of treating an individual having cancer, methods for assessing a response or monitoring the response of an individual to treatment with an anti-cancer therapy that includes an immunotherapy (e.g., a PD-L1 axis binding antagonist such as an anti-PD-L1 antibody (e.g., atezolizumab)) and a suppressive stromal antagonist (e.g., a TGF-beta antagonist), and related kits, anti-cancer therapies, and uses.

Description

[0001] sequence listing [0002] This application, containing a Sequence Listing, has been filed electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on November 5, 2018, is named 50474-172WO4_Sequence_Listing_11.5.18_ST25 and is 309,531 bytes in size. [0003] field of invention [0004] The present invention is directed to diagnostic and therapeutic methods for the treatment of cancer. Also provided are related kits and assays. [0005] Background of the invention [0006] Cancer remains one of the deadliest threats to human health. Cancer strikes nearly 1.3 million new patients each year in the United States and is the second leading cause of death after heart disease, accounting for about 1 in 4 deaths. It is also predicted that cancer may overtake cardiovascular disease as the number one cause of death within five years. Solid tumors are responsible for most of those deaths. Despite significant advances in m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): G01N33/574
CPCG01N33/57484G01N2333/495G01N2333/70596G01N2800/52C12Q1/6886C12Q2600/158C12Q2539/10C12Q2600/106A61K39/39558G01N33/57488
Inventor Y·关Y·森巴宝格鲁S·特里Y·王
Owner F HOFFMANN LA ROCHE & CO AG
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