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Therapeutic and diagnostic methods for cancer

a cancer and diagnostic method technology, applied in the field of cancer diagnostic methods and therapeutic and diagnostic methods, can solve the problems of poor outcomes, difficult timely detection and treatment, and cancer remains one of the most deadly threats to human health, and achieve the effect of inhibiting the binding of pd-l1 and inhibiting the binding of pd-l1

Inactive Publication Date: 2018-02-08
GENENTECH INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides methods and compositions for treating bladder cancer by targeting the PD-L1 axis. The invention features a therapeutically effective amount of a PD-L1 axis binding antagonist that can be administered to a patient with bladder cancer. The invention also includes a method of treating a patient with a luminal subtype tumor by administering a therapeutically effective amount of a PD-L1 axis binding antagonist. The invention is based on the discovery that a significant number of bladder cancer tumors express PD-L1, and that patients with bladder cancer who receive a therapeutic amount of a PD-L1 axis binding antagonist have a better overall survival and progression-free survival time compared to patients who do not receive the treatment. The objective response rate of the treatment is also improved.

Problems solved by technology

Cancer remains one of the most deadly threats to human health.
Cancers, or malignant tumors, metastasize and grow rapidly in an uncontrolled manner, making timely detection and treatment extremely difficult.
In particular, metastatic urothelial bladder cancer is associated with poor outcomes and represents a major unmet medical need with few effective therapies to date.

Method used

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  • Therapeutic and diagnostic methods for cancer
  • Therapeutic and diagnostic methods for cancer
  • Therapeutic and diagnostic methods for cancer

Examples

Experimental program
Comparison scheme
Effect test

example 1

tochemical (IHC) Analysis of PD-L1 Expression in Tumor Samples

[0444]Immunohistochemistry (IHC):

[0445]Formalin-fixed, paraffin-embedded tissue sections were deparaffinized prior to antigen retrieval, blocking and incubation with primary anti-PD-L1 antibody. Following incubation with secondary antibody and enzymatic color development, sections were counterstained and dehydrated in series of alcohols and xylenes before coverslipping.

The following protocol was used for IHC. The Ventana Benchmark XT or Benchmark Ultra system was used to perform PD-L1 IHC staining using the following reagents and materials:

Primary antibody: anti-PD-L1 Rabbit Monoclonal Primary Antibody

Specimen Type: Formalin-fixed paraffin embedded (FFPE) section of tumor samples

Epitope Recovery Conditions: Cell Conditioning, standard 1 (CC1, Ventana, cat #950-124)

Primary Antibody Conditions: 1 / 100, 6.5 μg / ml for 16 minutes at 36° C.

Diluent: Antibody dilution buffer (Tris-buffered saline containing carrier protein and BRI...

example 2

on Between PD-L1 Expression in Tumor-Infiltrating Immune Cells (ICs) and Response to Treatment with PD-L1 Axis Binding Antagonists

[0449]The association between PD-L1 expression in tumor-infiltrating immune cells within urothelial bladder cancer (UBC) tumors with benefit from treatment with PD-L1 axis binding antagonists was evaluated. The UBC patients studied were enrolled in an ongoing phase Ia study that includes a cohort of UBC patients (safety-evaluable UBC population=92). Key eligibility criteria included measurable disease per Response Evaluation Criteria In Solid Tumors (RECIST) v1.1 and an Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0 or 1. The UBC cohort originally enrolled patients with PD-L1 IC scores of IC2 / 3 but was then expanded to include all-comers, primarily recruiting PD-L1 IC0 / 1 patients. PD-L1 IC scores were scored as shown in Table 3. Atezolizumab (MPDL3280A) was administered intravenously (IV) every three weeks (q3w) at 15 mg / kg or 1200...

example 3

Study Examining the Association of Immunoblocker Signature and CTLA4 Expression Levels on Therapy with Response of UBC Patients to Atezolizumab

[0455]The association between response to treatment with atezolizimab with expression of a “immunoblocker” signature (including the genes CTLA4, BTLA, LAG3, HAVCR2, and PD1) during therapy was evaluated during the course of a Phase Ia clinical study that included a cohort of UBC patients.

[0456]As shown in FIG. 6, increased mRNA expression (as determined by a custom Nanostring assay) of the immunoblocker signature, as well as CTLA4, by T-cells by cycle 3, day 1 of treatment was associated with response to atezolizumab in UBC patients. Therefore, the expression levels of CTLA4, BTLA, LAG3, HAVCR2, and PD1 represent potential biomarkers for response of UBC patients to treatment with PD-L1 axis binding antagonists, including the anti-PD-L1 antibody atezolizumab.

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Abstract

The present invention provides therapeutic and diagnostic methods and compositions for cancer, for example, bladder cancer. The invention provides methods of treating bladder cancer, methods of determining whether a patient suffering from bladder cancer is likely to respond to treatment comprising a PD-L1 axis binding antagonist, methods of predicting responsiveness of a patient suffering from bladder cancer to treatment comprising a PD-L1 axis binding antagonist, and methods of selecting a therapy for a patient suffering from bladder cancer, based on expression levels of a biomarker of the invention (e.g., PD-L1 expression levels in tumor-infiltrating immune cells in a tumor sample obtained from the patient) and / or based on the determination of a tumor sample subtype.

Description

SEQUENCE LISTING[0001]The instant application contains a Sequence Listing which has been submitted electronically in ASCII format and is hereby incorporated by reference in its entirety. Said ASCII copy, created on Oct. 19, 2017, is named 50474-116003_Sequence_Listing_10.19.17_ST25 and is 23,641 bytes in size.FIELD OF THE INVENTION[0002]Provided herein are therapeutic and diagnostic methods and compositions for pathological conditions, such as cancer (e.g., bladder cancer (e.g., urothelial bladder cancer)), and methods of using PD-L1 axis binding antagonists. In particular, the invention provides biomarkers for patient selection and diagnosis, methods of treatment, articles of manufacture, diagnostic kits, and methods of detection.BACKGROUND[0003]Cancer remains one of the most deadly threats to human health. Cancers, or malignant tumors, metastasize and grow rapidly in an uncontrolled manner, making timely detection and treatment extremely difficult. In the U.S., cancer affects near...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07K16/28C12Q1/68G01N33/574
CPCC07K16/2827G01N33/57407C12Q1/6886C12Q2600/178C12Q2600/158C12Q2600/106C07K2317/76C07K2319/30C07K2317/24A61K2039/505G01N2333/70532G01N2800/52A61P13/10A61P35/00A61P35/04A61P43/00
Inventor HEGDE, PRITIKOWANETZ, MARCINFINE, GREGGMARIATHASAN, SANJEEVBOURGON, RICHARD
Owner GENENTECH INC
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