Biomarkers for determining the effectiveness of immune checkpoint inhibitors
Inventors
NISHIKAWA, HIROYOSHI • TOGASHI, YOSUKE • OHYAMA, YUKIYA • Yoshida, Takao • Takeda, Kazuhiko • KODA, KENICHI • Honda, Atsushi • OYAGI, ATSUSHI • KAKINUMA, TORU • Murata, Masayuki
Assignees
Ono Pharmaceutical Co Ltd • National Cancer Center Japan • National Cancer Center Korea
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Publication Number
US-12240903-B2
Publication Date
2025-03-04
Expiration Date
Abstract
A method for identifying a patient with malignant tumor on which the effect of an immune checkpoint inhibitor can be more expected, and agents for suppressing the progression of, suppressing the recurrence of, and/or treating malignant tumor, characterized by prescriptions based on identifying a patient with a malignant tumor on which the effect of an immune checkpoint inhibitor can be more expected, by analyzing evaluation items including combinations such as the PD-1 expression intensity, the percentage of the number of PD-1 expressing cells and the like in Treg cells and CD8+ T cells in tumor tissue or blood.
Core Innovation
The invention relates to suppressing progression of, suppressing recurrence of, and/or treating malignant tumor by patient selection using PD-1 expression in immune cell populations within tumor tissue. A tumor tissue sample from a patient with malignant tumor is obtained, and the amounts of a PD-1 expression intensity in CD8+ T cells and a PD-1 expression intensity in Treg cells in the tumor tissue sample are detected. Patients are identified based on a ratio of the PD-1 expression intensity in CD8+ T cells to the PD-1 expression intensity in Treg cells, including a ratio cutoff of 0.7 or more.
The approach also uses PD-1 expression quantified as PD-1-expressing cell percentages among CD8+ T cells and among Treg cells. In one criterion set, the patient satisfies at least one of a PD-1 intensity ratio cutoff or a ratio of percentages of PD-1-expressing cells among CD8+ T cells to among Treg cells, together with a minimum percentage of PD-1-expressing cells among CD8+ T cells. In other formulations, composite numerical criteria are calculated by multiplying a PD-1 intensity ratio by a PD-1-expressing cell percentage among CD8+ T cells, or by dividing the square of the CD8+ percentage by the Treg percentage.
After identifying that the patient satisfies the specified biomarker criterion, an effective amount of an agent containing a substance inhibiting an immune checkpoint is administered as an active ingredient to the patient in need thereof. The invention focuses on detecting PD-1 expression intensity and PD-1-expressing cell populations in CD8+ T cells and Treg cells in the same tumor tissue, and then using the resulting numerical biomarker thresholds to determine eligibility for immune-checkpoint inhibitor treatment.
Claims Coverage
The document provides four independent claims that each cover a method of suppressing progression/recurrence and/or treating malignant tumor via biomarker-based patient identification using PD-1 expression in CD8+ T cells and Treg cells, followed by administration of an immune-checkpoint-inhibiting agent. Across the independent claims, the inventive features are expressed as different numerical PD-1-based criteria and decision rules for when to administer the agent.
Pd-1 expression intensity ratio cutoff for cd8+ treg selection
Obtaining a tumor tissue sample, detecting PD-1 expression intensity in CD8+ T cells and PD-1 expression intensity in Treg cells, identifying that the patient has a ratio of the PD-1 expression intensity in CD8+ T cells to the PD-1 expression intensity in Treg cells in the tumor tissue of 0.7 or more, and administering an effective amount of an agent containing a substance inhibiting an immune checkpoint to the patient identified as having the ratio of 0.7 or more.
Combined pd-1 intensity or pd-1 percentage ratios with cd8+ pd-1 % threshold
Obtaining a tumor tissue sample, identifying that the patient satisfies at least one criterion and a CD8+ PD-1-expressing cell percentage threshold, wherein the criteria include a ratio of a PD-1 expression intensity in CD8+ T cells to a PD-1 expression intensity in Treg cells of 0.8 or more, or a ratio of a percentage of PD-1-expressing cells among CD8+ T cells to a percentage of PD-1-expressing cells among Treg cells of 0.8 or more, and the CD8+ threshold is 35% or more, and administering an effective amount of an agent containing a substance inhibiting an immune checkpoint to the patient identified as satisfying the criteria.
Multiplicative composite criterion using cd8+ pd-1 intensity ratio and cd8+ pd-1 %
Obtaining a tumor tissue sample, identifying that the patient satisfies criterion (a), and administering an effective amount of an agent containing a substance inhibiting an immune checkpoint to the patient in need thereof identified as satisfying criterion (a); wherein criterion (a) is a numerical value calculated by multiplying a ratio of a PD-1 expression intensity in CD8+ T cells to a PD-1 expression intensity in Treg cells by a percentage of the number of PD-1-expressing cells among the same CD8+ T cells, wherein the calculated numerical value is 25 or more.
Divided squared composite criterion using cd8+ pd-1 % and treg pd-1 %
Obtaining a tumor tissue sample, identifying that the patient satisfies criterion (a), and administering an effective amount of an agent containing a substance inhibiting an immune checkpoint to the patient identified as satisfying criterion (a); wherein criterion (a) is a numerical value calculated by dividing a square of a percentage of a number of PD-1-expressing cells among CD8+ T cells in tumor tissue from the patient by a percentage of a number of PD-1-expressing cells among Treg cells in the same tissue, wherein the numerical value is 25 or more.
Across the independent claims, patient selection for immune-checkpoint inhibitor administration is driven by PD-1 expression in CD8+ T cells and Treg cells in the same tumor tissue, using either a PD-1 expression intensity ratio cutoff, combined PD-1 intensity/percentage ratio criteria with a CD8+ PD-1-expressing cell percentage threshold, or composite numerical criteria derived from PD-1 expression intensity ratios and PD-1-expressing cell percentages.
Stated Advantages
Enables suppressing progression of, suppressing recurrence of, and/or treating malignant tumor by selecting patients based on PD-1 expression criteria in CD8+ T cells and Treg cells.
Provides specific numerical biomarker criteria for identifying patients to receive an immune-checkpoint-inhibiting agent.
Identifying malignant tumor patients likely to respond.
Documented Applications
Predicting responsiveness to immune checkpoint inhibitors in malignant tumors using PD-1 expression-related biomarker metrics involving CD8+ T cells and Treg cells.
Treatment context described for NSCLC and gastric cancer cohorts treated with nivolumab, including responder versus non-responder differences using PD-1/CD8/Treg biomarker metrics and derived reference cutoffs with PFS analyses.
Use of a test/measurement kit for quantifying PD-1 biomarker indices (Biomarkers 1-7) using methods such as flow cytometry, immunohistochemistry, FISH/CISH/SISH/DISH, mass cytometry, scRNA-seq, and mass imaging.
Biomarker-based patient selection for Nivolumab/immune checkpoint inhibition by comparing responder vs non-responder groups and using progression-free survival analysis.
Industrial applicability for identifying malignant tumor patients likely to respond.
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