Compositions and Methods for Cancer Immunotherapy
The invention provides compositions and improved methods for the treatment of cancer using IL-2 immunotherapy. The methods of the invention comprise administering to a patient, the fusion protein of SEQ ID NO: 1 at a dose of about 6 μg/kg/day to about 70 μg/kg/day and preferably at a dose of at least about 6 μg/kg/day to about 15 μg/kg/day or at a corresponding fixed per day dose based, for example, on an average about 60 to about 70 kg adult human or based, for example, on a child of about 12 kg to about 50 kg or more, wherein administration results in a dose dependent increase in circulating NK cells and CD8+ cells in a patient in the absence of a dose dependent increase in circulating immunosuppressive T regulatory (Treg) cells and preferably wherein the increase in circulating NK cells and CD8+ cells is greater relative to the increase in circulating T Treg cells.
1 . A method of treating cancer in a patient comprising administering to the patient a dose of at least about 6 μg/kg/day to about 15 μg/kg per day of the fusion protein of SEQ ID NO: 1.
2 . The method of claim 1 , wherein:
the dose is 6 μg/kg/day, 8 μg/kg/day, 10 μg/kg/day, 12 μg/kg/day, 14 μg/kg/day, or 15 μg/kg/day;
the patient has an improved safety profile as compared to a patient receiving high dose recombinant human IL-2 (rhlL-2) treatment, optionally wherein the patient has a lower risk of capillary leak syndrome or cytokine release syndrome;
the dose is administered by intravenous (I.V.) injection or infusion;
the dose is a fixed dose based on a 60-70 kg human;
the dose is a fixed dose and wherein the patient is a child, optionally wherein the child weighs about 15 kg to about 50 kg;
the method results in at least a partial response in the patient;
the method further comprises repeating administration of the fusion protein if the cancer reoccurs, or a new cancer develops in the patient; or
the mean fold change from baseline (FCB) in IFNγ present in a patient's peripheral blood, serum or plasma is at least about 2-fold, at least about 3-fold, at least about 4-fold, or at least about 5-fold.
3 . The method of claim 1 , wherein administration results in a dose dependent increase in circulating NK cells and CD8+ cells in a patient in the absence of a dose dependent increase in T regulatory (Treg) cells, optionally wherein:
the increase in circulating NK cells and CD8+ cells is at least 2 fold over baseline;
the increase in circulating NK cells and CD8+ cells is greater relative to the increase in circulating Treg cells;
an increase in circulating NK cells and CD8+ cells is greater relative to the increase in circulating Treg cells as compared to the increase in circulating NK cells and CD8+ cells relative to the increase in circulating Treg cells in a patient receiving high dose rhIL-2 treatment; and/or
the patient has a lower risk of capillary leak syndrome.
4 - 10 . (canceled)
11 . The method of claim 1 , wherein the cancer being treated is a solid tumor or a blood cancer, optionally wherein:
the solid tumor is a carcinoma, sarcoma or lymphoma;
the cancer being treated is renal cell carcinoma (RCC), melanoma, breast cancer, pancreatic cancer, prostate cancer, non-small cell lung cancer, liver cancer, colon and rectal cancer, bladder cancer, cervical cancer, thyroid cancer, esophageal cancer, oral cancer, mesothelioma, and non-melanoma skin cancer;
the blood cancer is leukemia, non-Hodgkin lymphoma, Hodgkin lymphoma and multiple myeloma; and/or
the size of the solid tumor is reduced.
12 - 15 . (canceled)
16 . The method of claim 1 , wherein the fusion protein of SEQ ID NO: 1 is administered by intravenous injection or infusion at a dose of at least about 6 μg/kg to about 15 μg/kg per day as a once a day administration for about 1 day to about 5 days, optionally wherein:
the fusion protein is administered once a day for at least about 2 consecutive days, at least about 3 consecutive days, at least about 4 consecutive days, or at least about 5 consecutive days;
the fusion protein is administered once a day on non-consecutive days for no more than about 5 total non-consecutive of days of administration; and/or
the fusion protein is administered followed by a rest period of at least about 9 consecutive days, optionally wherein the rest period is at least about 16 consecutive days.
17 - 23 . (canceled)
24 . The method of claim 1 , wherein the fusion protein of SEQ ID NO: 1 is administered in at least two courses of treatment, the first course of treatment comprising administration by intravenous injection or infusion at a dose of at least about 6 μg/kg to about 15 μg/kg per day for a period of about 1 to about 5 consecutive or non-consecutive days followed by a rest period of at least about 9 consecutive days followed by a second course of treatment comprising administering the fusion protein of SEQ ID NO: 1 by intravenous injection or infusion at a dose of at least about 6 μg/kg to about 15 μg/kg per day for a period of at least about 1 to at least about 5 consecutive or nonconsecutive days, followed by a rest period of at least about 9 consecutive days optionally wherein:
administration of the fusion protein for the first course of treatment and for the second course of treatment is for a period of 5 consecutive days or 5 non-consecutive days prior to a rest period of at least about 9 days, optionally wherein the rest period is at least about 16 days or wherein the rest period during the first course of treatment is about 9 consecutive days and wherein the rest period for the second course of treatment is about 16 or more consecutive days;
the second course of treatment begins at least about 24 hours or more after completion of the first course of treatment; and/or
the method further comprises a third course of treatment following the second course of treatment, optionally wherein:
the third course of treatment begins within about 24 hours or more after completion of the second course of treatment;
the method further comprises a fourth course of treatment following the third course of treatment, optionally wherein the fourth course of treatment begins about 24 hours or more after completion of the third course of treatment; and/or
wherein subsequent courses of treatment begin about 24 hours or more after completion of the prior course of treatment until the cancer is treated or until the patient is no longer benefitting from the treatment.
25 - 33 . (canceled)
34 . The method of claim 1 , further comprising co-administering to the patient a therapeutically effective amount of a therapeutic agent, optionally wherein the therapeutic agent is a PARP inhibitor, a cytotoxic agent, a chemotherapeutic agent, or an immune checkpoint inhibitor, optionally wherein the immune checkpoint inhibitor inhibits the interaction of PD-1 and PD-L1, optionally wherein the immune checkpoint inhibitor is pembrolizumab.
35 - 38 . (canceled)
39 . The method of claim 34 , wherein the fusion protein of SEQ ID NO: 1 is administered in at least two courses of treatment, the first course of treatment comprising administration by intravenous injection or infusion at a dose of at least about 6 μg/kg to about 15 μg/kg per day once a day for 1 to 5 days followed by a rest period of at least about 16 consecutive days followed by a second course of treatment comprising administering by intravenous injection or infusion at a dose of at least about 6 μg/kg to about 15 μg/kg per day for a period 1 to 5 consecutive days, followed by a rest period of at least about 16 consecutive days and wherein the pembrolizumab is co-administered once during the 1 to 5 days of administration during the first course and second course of treatment.
40 . The method of claim 24 , wherein:
the fusion protein is administered once a day for at least about 2 consecutive days at least about 3 consecutive days, at least about 4 consecutive days, or at least about 5 consecutive days;
the fusion protein of SEQ D NO: 1 is administered once a day on non-consecutive days for no more than about 5 total non-consecutive of days of administration;
the second course of treatment begins at least about 24 hours or more after completion of the first course of treatment; and/or
the method further comprises a third course of treatment following the second course of treatment, optionally wherein:
the third course of treatment begins within about 24 hours or more after completion of the second course of treatment;
the method further comprises a fourth course of treatment following the third course of treatment, optionally wherein the fourth course of treatment begins about 24 hours or more after completion of the third course of treatment; and/or
wherein subsequent courses of treatment begin about 24 hours or more after completion of the prior course of treatment until the cancer is treated or until the patient is no longer benefitting from the treatment.
41 - 50 . (canceled)
51 . The method of claim 39 , wherein the pembrolizumab is co-administered prior to, simultaneously with, or subsequent to, administration of the fusion protein of SEQ ID NO:1, optionally wherein:
the pembrolizumab is co-administered in a separate composition from the fusion protein of SEQ ID NO: 1;
the pembrolizumab is co-administered in an amount of 200 mg by I.V. injection or infusion;
the pembrolizumab is administered on the first day of administration of the fusion protein of SEQ ID NO: 1 during the first course of treatment;
the pembrolizumab is administered on the first day of administration of the fusion protein of SEQ ID NO: 1 during the second course of treatment; and/or
the pembrolizumab is administered on the first day of administration of the fusion protein of SEQ ID NO: 1 during subsequent courses of treatment.
52 - 56 . (canceled)
57 . The method of claim 34 , resulting in a dose dependent increase in circulating NK cells and CD8+ cells in a patient in the absence of a dose dependent increase in T regulatory (Treg) cells, optionally wherein:
the dose dependent increase in circulating NK cells and CD8+ cells is greater than the non-dose dependent increase in Treg cells;
the patient has an improved safety profile as compared to a patient receiving high dose recombinant human IL-2 (rhlL-2) treatment;
the patient has a lower risk of cytokine release syndrome as compared to a patient receiving high dose recombinant human IL-2 (rhlL-2) treatment; and/or
the patient has a lower risk of capillary leak syndrome as compared to a patient receiving high dose recombinant human IL-2 (rhlL-2) treatment.
58 - 72 . (canceled)
73 . A method of treating cancer in a patient comprising administering to the patient a dose of at least about 40 μg/kg to about 70 μg/kg per day of the fusion protein of SEQ ID NO: 1 once weekly.
74 . The method of claim 71 , wherein the daily dose is about 50 μg/kg to about 60 μg/kg.
75 . The method of claim 73 , comprising administering to the patient a dose of at least about 50 μg/kg to about 60 μg/kg per day of the fusion protein of SEQ ID NO: 1 once weekly, resulting in a dose dependent increase in circulating NK cells and CD8+ cells in a patient in the absence of a dose dependent increase in circulating T regulatory (Treg) cells, and wherein the increase in circulating NK cells and CD8+ cells relative to the increase in circulating T regulatory (Treg) is greater compared to the increase in circulating NK cells and CD8+ cells relative to the increase in circulating T regulatory (Treg) in a patient receiving high dose recombinant human IL-2 (rhlL-2) treatment, and
wherein the patient has a lower risk of capillary leak syndrome as compared to a patient receiving high dose recombinant human IL-2 (rhlL-2) treatment, optionally wherein the dose is administered by intravenous injection or infusion.
76 . (canceled)
77 . A pharmaceutical composition comprising about 0.4 to about 1 mg of the fusion protein of SEQ ID NO: 1.
78 . A method of treating cancer in a patient comprising administering to the patient a daily dose of at least about 3 μg/kg to about 5.5 μg/kg of the fusion protein of SEQ ID NO: 1 wherein administration results in a dose dependent increase in circulating NK cells and CD8+ cells in a patient in the absence of a dose dependent increase in circulating T regulatory (Treg) cells and wherein the increase in circulating NK cells and CD8+ cells is greater relative to the increase in circulating T regulatory cells (Treg).
79 - 84 . (canceled)
85 . A method for treating cancer in a patient comprising intravenously administering to the patient a dose of at about 16 μg/kg/day to about 70 μg/kg/day of the fusion protein of SEQ ID NO: 1 or a corresponding fixed dose based on an about 60-70 kg adult or about 12 kg to 50 kg or more child.
86 . The method of claim 85 , wherein:
the dose is about 16 μg/kg/day to about 50 μg/kg/day of the fusion protein of SEQ ID NO: 1 or a corresponding fixed dose based on an about 60-70 kg adult or about 12 kg to 50 kg or more child, optionally wherein the corresponding fixed dose is about 5 μg to about 3 mg;
the mean fold change from baseline (FCB) in IFN′ present in a patient's peripheral blood, serum or plasma is at least about 2-fold, at least about 3-fold, at least about 4-fold, or at least about 5-fold; and/or
the fusion protein of SEQ ID NO: 1 is administered on non-consecutive days, optionally wherein:
the fusion protein of SEQ ID NO: 1 is administered once every 7 days, once every 14 days or once every 21 days of a treatment cycle;
the fusion protein of SEQ ID NO: 1 is administered on days 1, 7, 14 and 21 of a treatment cycle;
the fusion protein of SEQ ID NO: 1 is administered on days 1 and 14 of a treatment cycle; or
the fusion protein of SEQ ID NO: 1 is administered on days 1 and 21 of a treatment cycle.
87 - 96 . (canceled)
97 . The method of claim 2 , wherein: the mean fold change from baseline in IL-6 is less than 4-fold; and/or the dose of the fusion protein of SEQ ID NO: 1 is about 6 μg/kg/day or about 8 μg/kg/day.
98 - 101 . (canceled)
102 . The method of claim 85 , wherein: the mean fold change from baseline in IL-6 is less than 4-fold; and/or the dose of the fusion protein of SEQ ID NO: 1 is about 30 μg/kg/day or about 50 μg/kg/day.
103 . (canceled)