Low, immune enhancing, dose mtor inhibitors and uses thereof

Abstract

The present invention relates, in part, to compositions and methods for enhancement of an immune response by partial mTOR inhibition, e.g., with low, immune enhancing, doses of an mTOR inhibitor, such as RAD001.

What is claimed is: 
     
         1 . A method of promoting an immune response in a subject, comprising,
 administering to the subject a low, immune enhancing, dose of an mTOR inhibitor,   thereby enhancing or promoting an immune response in the subject.   
     
     
         2 . The method of  claim 1 , wherein the mTOR inhibitor is an allosteric mTOR inhibitor or a catalytic inhibitor. 
     
     
         3 . The method of  claim 1 , wherein the mTOR inhibitor is RAD001 or rapamycin. 
     
     
         4 . The method of  claim 2 , wherein the catalytic inhibitor is a kinase inhibitor. 
     
     
         5 . The method of  claim 4 , wherein the kinase inhibitor is selective for mTOR or is selected from BEZ235 and CCG168. 
     
     
         6 . The method of  claim 1 , wherein the dose comprises an allosteric and a catalytic mTOR inhibitor. 
     
     
         7 . The method of  claim 1 , wherein the mTOR inhibitor is administered for an amount of time sufficient one or more of the following to occur:
 i) a decrease in the number of PD-1 positive immune effector cells;   ii) an increase in the number of PD-1 negative immune effector cells;   iii) an increase in the ratio of PD-1 negative immune effector cells/PD-1 positive immune effector cells;   iv) an increase in the number of naive T cells;   v) an increase in the expression of one or more of the following markers: CD62L high , CD127 high , CD27 + , and BCL2, e.g., on memory T cells, e.g., memory T cell precursors;   vi) a decrease in the expression of KLRG1, e.g., on memory T cells, e.g., memory T cell precursors; or   vii) an increase in the number of memory T cell precursors, e.g., cells with any one or combination of the following characteristics: increased CD62L high  increased CD127 high , increased CD27 + , decreased KLRG1, and increased BCL2;   and wherein i), ii), iii), iv), v), vi), or vii) occurs at least transiently, as compared to a non-treated subject.   
     
     
         8 . The method of  claim 1 , wherein the method comprises inhibiting a negative immune response mediated by the engagement of PD-1 with PD-L1 or PD-L2. 
     
     
         9 . The method of  claim 1 , which comprises increasing the number of T cells capable of proliferation, cytotoxic function, secreting cytokines, or activation. 
     
     
         10 . The method of  claim 1 , wherein the administering results in the partial, but not total, inhibition of mTOR for at least 1, 5, 10, 20, 30, or 60 days. 
     
     
         11 . The method of  claim 1 , wherein the dose of an mTOR inhibitor is associated with mTOR inhibition of at least 5% but no more than 90%, as measured by p70 S6K inhibition. 
     
     
         12 . The method of  claim 11 , wherein the mTOR inhibitor comprises RAD001. 
     
     
         13 . The method of  claim 1 , wherein administering comprises administering, once per week, in an immediate release dosage form, 0.1 to 20, 0.5 to 10, 2.5 to 7.5, 3 to 6, or about 5 mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         14 . The method of  claim 1 , wherein administering comprises administering, once per week, in an immediate release dosage form, about 5 mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         15 . The method of  claim 1 , wherein administering comprises administering, once per week, in a sustained release dosage form, 0.3 to 60, 1.5 to 30, 7.5 to 22.5, 9 to 18, or about 15 mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         16 . The method of  claim 1 , wherein administering comprises administering, once per week, in a sustained release dosage form, about 15 mgs of RAD001 or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         17 . The method of  claim 1 , wherein administering comprises administering, once per day, in an immediate release dosage form, 0.005 to 1.5, 0.01 to 1.5, 0.1 to 1.5, 0.2 to 1.5, 0.3 to 1.5, 0.4 to 1.5, 0.5 to 1.5, 0.6 to 1.5, 0.7 to 1.5, 0.8 to 1.5, 1.0 to 1.5, 0.3 to 0.6, or about 0.5 mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         18 . The method of  claim 1 , wherein administering comprises administering once per day, in an immediate release dosage form, about 0.5 mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         19 . The method of  claim 1 , wherein administering comprises administering, once per day, in a sustained release dosage form, 0.015 to 4.5, 0.03 to 4.5, 0.3 to 4.5, 0.6 to 4.5, 0.9 to 4.5, 1.2 to 4.5, 1.5 to 4.5, 1.8 to 4.5, 2.1 to 4.5, 2.4 to 4.5, 3.0 to 4.5, 0.9 to 1.8, or about 1.5 mgs mgs of RAD001, or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         20 . The method of  claim 1 , wherein administering comprises administering, once per week, in a sustained release dosage form, 0.1 to 30, 0.2 to 30, 2 to 30, 4 to 30, 6 to 30, 8 to 30, 10 to 30, 1.2 to 30, 14 to 30, 16 to 30, 20 to 30, 6 to 12, or about 10 mgs of RAD001 or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         21 . The method of  claim 1 , wherein the mTOR inhibitor is RAD001 and the dose provides for a trough level of RAD001 in a range of between about 0.1 and 3 ng/ml, between 0.3 or less and 3 ng/ml, or between 0.3 or less and 1 ng/ml, or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         22 . The method of  claim 1 , wherein the subject has cancer and the method comprises
 promoting the subject's immune response to the cancer.   
     
     
         23 . The method of  claim 22 , wherein the subject was selected on the basis of having cancer. 
     
     
         24 . The method of  claim 22 , wherein a cell of the cancer expresses PD-L1 or PD-L2. 
     
     
         25 . The method of  claim 22 , wherein a cell in the cancer microenvironment expresses PD-L1 or PD-L2. 
     
     
         26 . The method of  claim 22 , wherein the cancer comprises a solid tumor. 
     
     
         27 . The method of  claim 22 , wherein the cancer is a hematological cancer. 
     
     
         28 . The method of  claim 22 , wherein the cancer is selected from Table 1. 
     
     
         29 . The method of  claim 22 , wherein the cancer is melanoma. 
     
     
         30 . The method of  claim 22 , further comprising administering a second treatment to the subject. 
     
     
         31 . The method of  claim 30 , wherein the second treatment is a chemotherapeutic, radiation, a cellular therapy, or bone marrow transplant. 
     
     
         32 . The method of  claim 30 , comprising administering a second treatment that kills T cells. 
     
     
         33 . The method of  claim 32 , wherein the second treatment is radiation or cytotoxic chemotherapy. 
     
     
         34 . The method of  claim 30 , wherein the mTOR inhibitor is administered prior to, simultaneously with, or after the initiation of the second treatment. 
     
     
         35 . The method of any of  claim 22 , comprising treating a cancer from Table 1, and administering a treatment listed in Table 1 for that cancer. 
     
     
         36 . The method of  claim 1 , wherein the subject is immunocompromised. 
     
     
         37 . The method of  claim 1 , wherein the subject is HIV+ or has AIDs. 
     
     
         38 . The method of  claim 1 , wherein the subject has an infectious disease. 
     
     
         39 . The method of  claim 1 , wherein the subject has an impaired immune response. 
     
     
         40 . The method of  claim 1 , wherein the subject is immunoscenescent. 
     
     
         41 . The method of  claim 1 , comprising treating the subject for an age related condition. 
     
     
         42 . The method of  claim 41 , wherein the age related condition is selected from the group consisting of sarcopenia, skin atrophy, muscle wasting, brain atrophy, atherosclerosis, arteriosclerosis, pulmonary emphysema, osteoporosis, osteoarthritis, high blood pressure, erectile dysfunction, dementia, Huntington's disease, Alzheimer's disease, cataracts, age-related macular degeneration, prostate cancer, stroke, diminished life expectancy, impaired kidney function, and age-related hearing loss, aging-related mobility disability (e.g., frailty), cognitive decline, age-related dementia, memory impairment, tendon stiffness, heart dysfunction such as cardiac hypertrophy and systolic and diastolic dysfunction, immunosenescence, cancer, obesity, and diabetes. 
     
     
         43 . The method of  claim 1 , comprising, enhancing an immune response to an antigen in the subject. 
     
     
         44 . The method of  claim 43 , further comprising administering the antigen or a vaccine to the subject. 
     
     
         45 . The method of  claim 44 , wherein prior to the step of administering, the method comprises a step of identifying a subject having an impaired immune response to an antigen. 
     
     
         46 . The method of  claim 44 , wherein the antigen is an influenza antigen. 
     
     
         47 . The method of  claim 46 , wherein the antigen is selected from the influenza subgroup consisting of H1N1, H2N3, and B influenza subtypes. 
     
     
         48 . The method of  claim 44 , wherein the antigen is a pneumococcal antigen. 
     
     
         49 . The method of  claim 44 , wherein the antigen and the mTOR inhibitor are co-administered. 
     
     
         50 . The method of any of  claim 44 , wherein the antigen and the mTOR inhibitor are administered sequentially. 
     
     
         51 . The method of  claim 1 , wherein the subject is less than 65 years old. 
     
     
         52 . The method of  claim 1 , wherein the subject does not receive a vaccine while the mTOR inhibitor is present at levels which promote the immune response. 
     
     
         53 . The method of  claim 52 , wherein the vaccine is an anti-cancer vaccine or a vaccine against an infectious agent. 
     
     
         54 . The method of  claim 52 , wherein the vaccine is a therapeutic vaccine for a neurological disorder or Alzheimer's disease. 
     
     
         55 . The method of  claim 1 , wherein the subject does not receive a vaccine within 10, 20, 30, 40, 50, 60, 70, 80, or 90 days prior to or after initiation of the low, immune enhancing, dose of the mTOR inhibitor. 
     
     
         56 . The method of  claim 1 , wherein the low, mTOR inhibitor is administered at the time of, or after vaccination. 
     
     
         57 . A method of evaluating a subject for treatment with a low, immune enhancing, dose of mTOR inhibitor, to promote or enhance an immune response to an influenza vaccine or antigen, comprising:
 determining a baseline or pre-immunization level of anti-influenza antibody,   wherein a relatively low baseline or pre-immunization level of anti-influenza antibody is predictive of a greater mTOR inhibitor-associated increase in antibody titer for the influenza antigen,   thereby evaluating the subject.   
     
     
         58 . The method of  claim 57 , further comprising comparing the determined level with a reference value, wherein a value less than or equal to the reference value is indicative of a greater mTOR inhibitor-associated increase in antibody titer. 
     
     
         59 . The method of  claim 57 , wherein responsive to a determined level of antibody titer the subject is classified as to likelihood of benefiting from a low, immune enhancing, dose of mTOR inhibitor. 
     
     
         60 . The method of  claim 57 , wherein responsive to a determined level of antibody titer the subject is administered a low, immune enhancing, dose of mTOR inhibitor. 
     
     
         61 . The method of  claim 57 , wherein the determining step comprises
 determining if the baseline or pre-immunization titer of anti-influenza antibody of the subject is equal to or less than 1:40; and   responsive to said determination, classifying the subject as to the likelihood of benefiting from a low, immune enhancing, dose of an mTOR inhibitor, or selecting a course of therapy for said subject.   
     
     
         62 . The method of  claim 57 , wherein the mTOR inhibitor is RAD001. 
     
     
         63 . The method of  claim 1 , wherein the subject is a human. 
     
     
         64 . A vaccine adjuvant comprising about 0.005 mg to 1.5 mg of the mTOR inhibitor RAD001, or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         65 . The vaccine adjuvant of  claim 64 , comprising an amount of an mTOR inhibitor sufficient to inhibit P70 S6 kinase activity in a cell by no greater than 80%. 
     
     
         66 . The vaccine adjuvant of  claim 64 , wherein said mTOR inhibitor is a rapamycin or a rapalog. 
     
     
         67 . The vaccine adjuvant of any of  claim 64 , comprising a 0.01-1 mg, 0.01-0.7 mg, 0.01-0.5 mg, or 0.1-0.5 mg of RAD001 or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         68 . The vaccine adjuvant of any of  claim 64 , comprising 0.5 mg of RAD001 or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         69 . A composition comprising
 (a) a vaccine antigen; and   (b) about 0.005 mg to 1.5 mg of the mTOR inhibitor RAD001, or a bioequivalent dose of a different mTOR inhibitor   
     
     
         70 . The composition of  claim 69 , wherein said composition comprises about 0.01-1 mg, about 0.01-0.7 mg, about 0.01-0.5 mg, or about 0.1-0.5 mg of RAD001, or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         71 . The composition of  claim 69 , comprising about 0.5 mg of RAD001 or a bioequivalent dose of a different mTOR inhibitor. 
     
     
         72 . The composition of  claim 69 , wherein said composition comprises an amount of an mTOR inhibitor sufficient to inhibit P70 S6 kinase activity by no greater than 80% in a subject to which said composition is administered. 
     
     
         73 . The composition of  claim 69 , wherein said composition produces at least a 1.2 fold increase in immune response as compared to placebo in a subject to which said composition is administered. 
     
     
         74 . The composition of  claim 69 , wherein said mTOR inhibitor is a rapamycin or a rapalog. 
     
     
         75 . The composition of  claim 69 , wherein said vaccine antigen is derived from influenza. 
     
     
         76 . The composition of  claim 69 , wherein said vaccine antigen is selected from the group consisting of H1N1, H2N3, and B influenza subtypes. 
     
     
         77 . The composition of  claim 69 , wherein said vaccine antigen is derived from pneumococcus.