Biomarkers for determining the efficacy of immune checkpoint inhibitors
Inventors
NISHIKAWA, HIROYOSHI • OHYAMA, YUKIYA • Honda, Atsushi • OYAGI, ATSUSHI • KAKINUMA, TORU • Murata, Masayuki
Assignees
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Publication Number
US-12571799-B2
Publication Date
2026-03-10
Expiration Date
Abstract
A method for identifying a patient with malignant tumor which can be expected to benefit more from an immune checkpoint inhibitor, and agent for suppressing the progression of, suppressing the recurrence of, and/or treating malignant tumor, being prescribed based thereon, comprising use of a combination of two sets of evaluation items and specific condition defined by each of combination thereof.
Core Innovation
The patent describes methods for suppressing a progression of, suppressing a recurrence of and/or treating a malignant tumor using an immune checkpoint inhibitor. The method includes identifying a patient based on specific conditions evaluated in tumor tissue or blood prior to administration of the immune checkpoint inhibitor.
The conditions are defined using quantitative relationships among immune-cell subsets and PD-1 expression metrics, including CCR7 expressing cells among CD8+ T cells, PD-1 expression in CD8+ T cells, and PD-1 expression in Foxp3+ T cells. The quantitative patient-identification conditions incorporate mathematical expressions involving percentages and numbers of PD-1 expressing cells, ratios of mean fluorescence intensity (MFI) values for PD-1 expression, and transformations such as a square root and Log10.
Additional conditions relate PD-1 expression in CD3+ cells to PD-1 expression in Fraction II Treg cells, combined with a percentage of PD-1 expressing cells among CD4+ T cells. A further patient-identification approach evaluates a combination of items corresponding to PD-1 expressing cells among Fraction III Treg cells, Foxp3+ T cells, Fraction II Treg cells, a square root of a ratio of PD-1 MFI in CD8+ T cells to PD-1 MFI in Foxp3+ T cells, and PD-1 expressing cells among CD4+ T cells.
In both approaches, the identified patient is treated by administering an effective dose of the immune checkpoint inhibitor.
Claims Coverage
The provided material includes two independent method claims. Across these independent claims, the inventive features are directed to pre-administration patient identification using formula-based biomarker thresholds involving PD-1 expression metrics, CCR7 expressing cells, T-cell/Treg subsets, and MFI-based ratios, followed by administering an effective dose of an immune checkpoint inhibitor.
Biomarker-defined eligibility using CCR7+ CD8+ T cells and PD-1 MFI ratios with square-root and Log10 thresholds
A method that identifies a patient having any one of conditions (a) to (c) based on tumor tissue or blood measurements prior to administration of an immune checkpoint inhibitor, where condition (a) uses CCR7 expressing cells among CD8+ T cells together with square roots of ratios of PD-1 MFI in CD8+ T cells to PD-1 MFI in Foxp3+ T cells, condition (b) uses numbers of PD-1 expressing cells among CD8+ T cells together with Log10 expressions and square roots of the same PD-1 MFI ratios, and condition (c) uses a square root of a ratio of PD-1 MFI in CD3+ cells to PD-1 MFI in Fraction II Treg cells together with a percentage of PD-1 expressing cells among CD4+ T cells.
Biomarker-defined eligibility using PD-1 on multiple Treg/Foxp3 fractions and CD8+ cells with selectable formula thresholds
A method that identifies a patient, prior to administration of an immune checkpoint inhibitor, by requiring that a combination of items (1) and (2) is satisfied, where item (1) is any one selected from PD-1 expressing cell percentages among Fraction III Treg cells, among Foxp3+ T cells, among Fraction II Treg cells, a square root of a ratio of PD-1 MFI in CD8+ T cells to PD-1 MFI in Foxp3+ T cells, or among CD4+ T cells, and item (2) is a percentage of PD-1 expressing cells among the CD8+ T cells, with the resulting pair meeting formula-based conditions (a) to (e) corresponding to the selected item (1).
Across the independent claims provided, the inventive coverage is directed to selecting patients for immune checkpoint inhibitor treatment using pre-treatment tumor tissue or blood biomarker conditions expressed as formula-based thresholds involving PD-1 expressing cell percentages and numbers, CCR7+ CD8+ T cell metrics, Treg/Foxp3-associated PD-1 MFI ratios, and transformations including square root and Log10, followed by administering an effective dose of the immune checkpoint inhibitor.
Stated Advantages
Documented Applications
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