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US 12,571,799 B2Granted
Biomarkers for determining the efficacy of immune checkpoint inhibitors
AssigneesOno Pharmaceutical Co., Ltd., National Cancer Center
InventorsHiroyoshi Nishikawa, Yukiya Ohyama, Atsushi Honda, Atsushi Oyagi, Toru Kakinuma, Masayuki Murata
Life of this patent
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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.
Claims14
A method for suppressing a progression of, suppressing a recurrence of and/or treating a malignant tumor, said method comprising:
- (I) identifying a patient having any one of the conditions selected from the following items (a) to (c), wherein:
- (a) is condition (a1) represented by formula:
- Y1≥a1-1×X1+Y1-1
- wherein Y1 represents a percentage (%) of CCR7 expressing cells among CD8+ T cells in a tumor tissue or blood from the patient with the malignant tumor prior to administration of an immune checkpoint inhibitor, a1-1 represents about −637, X1 represents a square root of a ratio of mean fluorescence intensity (MFI) of PD-1 expression in the CD8+ T cells to MFI of PD-1 expression in Foxp3+ T cells in the tumor tissue or blood from said patient, and Y1-1 represents an arbitrary value from about 784 to about 914, or
- condition (a2) represented by two formulas:
- Y1≤a1-2×X1+Y1-2 and Y1≤a1-3×X1+Y1-3,
- wherein Y1 represents a percentage (%) of CCR7 expressing cells among the CD8+ T cells in the tumor tissue or blood from said patient, a1-2 represents about −24.0, X1 represents a square root of a ratio of MFI of PD-1 expression in the CD8+ T cells to MFI of PD-1 expression in the Foxp3+ T cells in the tumor tissue or blood from said patient, Y 1-2 represents an arbitrary value from about 39.0 to about 50.9, a1-3 represents about 666, and Y1-3 represents an arbitrary value from about −652 to about −522;
- (b) is condition (b1) represented by formula:
- Log10(Y3+1)≥a3-1×X3+Y3-1 or Log10(Y3)≥a3-1×X3+Y3-1,
- wherein Y3 represents a number of PD-1 expressing cells among the CD8+ T cells in the tumor tissue or blood from said patient, a3-1 represents about −1.59, X3 represents the square root of the ratio of MFI of PD-1 expression in the CD8+ T cells to MFI of PD-1 expression in the Foxp3+ T cells in the tumor tissue or blood from of said patient, and Y3-1 represents an arbitrary value from about 4.09 to about 4.89, or
- condition (b2) represented by formula:
- Log10(Y3+1)≥a3-2×X3+Y3-2 or Log10(Y3)≥a3-2×X3+Y3-2,
- wherein Y3 represents a number of PD-1 expressing cells among the CD8+ T cells in the tumor tissue or blood from said patient, a3-2 represents about −9.05, X3 represents the square root of the ratio of MFI of PD-1 expression in the CD8+ T cells to MFI of PD-1 expression in the Foxp3+ T cells in the tumor tissue or blood from said patient, and Y3-2 represents an arbitrary value from about 10.7 to about 13.3;
- and
- (c) the condition is represented by formula:
- a8-1×X8+Y8-1≤Y8≤a8-2×X8+Y8-2,
- wherein Y8 represents a square root of a ratio of MFI of PD-1 expression in CD3+ cells to MFI of PD-1 expression in Fraction II Treg cells in the tumor tissue or blood from said patient, a8-1 represents about −0.00338, X8 represents a percentage (%) of PD-1 expressing cells among CD4+ T cells in the tumor tissue or blood from said patient, Y8-1 represents an arbitrary value from about 0.939 to about 1.37, a8-2 represents about 0.270, and Y8-2 represents an arbitrary value from about −6.98 to about −0.654;
- and
- (II) administering an effective dose of the immune checkpoint inhibitor to the patient identified in (I).
16 more elements
A method for suppressing a progression of, suppressing a recurrence of and/or treating a malignant tumor, said method comprising:
- (I) identifying a patient having a following condition:
- in a tumor tissue or blood from said patient prior to administration of an immune checkpoint inhibitor a combination of items (1) and (2) below:
- (1) any one selected from items (i) to (v):
- (i) a percentage (%) of PD-1 expressing cells among Fraction III Treg cells,
- (ii) a percentage (%) of PD-1 expressing cells among Foxp3+ T cells,
- (iii) a percentage (%) of PD-1 expressing cells among Fraction II Treg cells,
- (iv) a square root of a ratio of MFI of PD-1 expression in CD8+ T cells to MFI of PD-1 expression in the Foxp3+ T cells, and
- (v) a percentage (%) of PD-1 expressing cells among CD4+ T cells;
- and
- (2) a percentage (%) of PD-1 expressing cells among the CD8+ T cells,
- meets conditions selected from items (a) to (e), corresponding to items (i) to (v), respectively:
- (a) condition represented by formula:
- Y2≥a2-1×X2+Y2-1,
- wherein Y2 represents the percentage (%) of item (i), a2-1 represents about 0.765, X2 represents the percentage (%) of item (2), and Y2-1 represents an arbitrary value from about 50.6 to about 59.2, or formula:
- Y2≤a2-2×X2+Y2-2,
- wherein Y2 represents the percentage (%) of item (i), a2-2 represents about 1.56, X2 represents the percentage (%) of item (2), and Y2-2 represents an arbitrary value from about −44.1 to about 14.5;
- (b) condition represented by formula:
- Y5≥a5×X5+Y5-1,
- wherein Y5 represents the percentage (%) of item (ii), as represents about 2.34, X5 represents the percentage (%) of item (2), and Y5-1 represents an arbitrary value from about −117 to about 131;
- (c) condition represented by formula:
- Y6≥a6-1×X6+Y6-1,
- wherein Y6 represents the percentage (%) of item (iii), a6-1 represents about 1.69, X6 represents the percentage (%) of item (2), and Y6-1 represents an arbitrary value from about 21.4 to about 44.1, or formula:
- Y6≤a6-2×X6+Y6-2,
- wherein Y6 represents the percentage (%) of item (iii), a6-2 represents about 1.78, X6 represents the percentage (%) of item (2), and Y6-2 represents an arbitrary value from about −80.6 to about −21.0;
- (d) condition represented by formula:
- Y4≥a4-1×X4+Y4-1,
- wherein Y4 represents a square root of item (iv), a4-1 represents about −0.00273, X4 represents the percentage (%) of item (2), and Y4-1 represents an arbitrary value from about 0.905 to about 1.46, or formula:
- Y4≥a1-2×X4+Y4-2,
- wherein Y4 represents the square root of item (iv), a4-2 represents about −0.0294, X4 represents the percentage (%) of item (2), and Y4-2 represents an arbitrary value from about 2.18 to about 3.31;
- and
- (e) condition represented by formula:
- Y7≤a7-1×X7+Y7-1,
- wherein Y7 represents the percentage (%) of item (v), a7-1 represents about 0.227, X7 represents the percentage (%) of item (2), and Y7-1 represents an arbitrary value from about −13.9 to about 4.03, or formula:
- Y7≤a7-2×X7+Y7-2,
- wherein Y7 represents the percentage (%) of item (v), a7-2 represents about 3.32, X7 represents the percentage (%) of item (2), and Y7-2 represents an arbitrary value from about −199 to about 58.2;
- and
- (II) administering an effective dose of the immune checkpoint inhibitor to the patient identified in (I).
34 more elements
Dependencies are inferred from the claim text.