Multiple-variable IL-2 dose regimen for treating immune disorders

1. A method of treating a subject afflicted with graft-versus-host disease (GVHD) comprising:

a) administering to the subject an induction regimen comprising administering to the subject interleukin-2 (IL-2) at a dose that increases the subject's plasma IL-2 level and increases the subject's ratio of regulatory T lymphocytes (Tregs) to conventional T lymphocytes (Tcons) (Tregs:Tcons), wherein the induction regimen dose is less than about 6.0×10 6 IU/m 2 /day; and

b) subsequently administering to the subject a maintenance regimen comprising administering to the subject an IL-2 maintenance dose that is higher than the induction regimen dose and that i) further increases the subject's plasma IL-2 level and ii) further increases the ratio of Tregs to Tcons, thereby treating the subject.

2. The method of claim 1 , wherein the IL-2 maintenance regimen increases the subject's plasma IL-2 level beyond the peak plasma IL-2 level induced by the induction regimen.

3. The method of claim 1 , wherein the induction regimen dose is about 0.3×10 6 IU/m 2 /day to about 3.0×10 6 IU/m 2 /day.

4. The method of claim 1 , wherein the administration of the induction regimen comprises administration once per day.

5. The method of claim 1 , wherein the Tregs:Tcons in the maintenance regimen is increased by and maintained at a level at least 20% over the maximal Tregs:Tcons during the induction regimen.

6. The method of claim 1 , wherein the maintenance regimen dose is

i) at least about 20% higher than the induction regimen dose;

ii) about 0.3×10 6 IU/m 2 /day to about 3.0×10 6 IU/m 2 /day; and/or

iii) less than about 6.0×10 6 IU/m 2 /day.

7. The method of claim 1 , wherein the administration of the maintenance regimen comprises administration once per day for 1 day, 2 consecutive days, 3 consecutive days, 4 consecutive days, 5 consecutive days, 6 consecutive days, 7 consecutive days, 8 consecutive days, 9 consecutive days, 10 consecutive days, 11 consecutive days, 12 consecutive days, 13 consecutive days, or at least 14 consecutive days.

8. The method of claim 1 , wherein the IL-2

i) is administered in a pharmaceutically acceptable formulation; and/or

ii) is administered by an administration route selected from the group consisting of subcutaneous, intravenous, intraperitoneal, and intramuscular.

9. The method of claim 1 , wherein the IL-2 is administered subcutaneously.

10. The method of claim 1 , wherein the subject

i) has had an inadequate response to systemic steroids;

ii) has persistent or recurrent chronic GVHD despite at least 2 prior systemic therapies including steroids; and/or

iii) has had extra-corporeal photopheresis (ECP) prior to IL-2 administration.

11. The method of claim 1 , wherein the subject is a mammal, an animal model of an immune disorder or a human.

12. The method of claim 1 , wherein the subject is a pediatric subject or wherein GVHD is chronic GVHD.

13. The method of claim 1 , wherein the induction regimen and/or the maintenance regimen further comprises administration of one or more additional therapies to treat the immune disorder.

14. The method of claim 13 , wherein the one or more additional therapies is administration of Tregs and the Tregs are administered

i) with T cells other than Tregs; and/or

ii) at between about 0.1×10 6 cells/kg body weight to 1.0×10 6 cells/kg body weight.

15. The method of claim 14 , wherein the one or more additional therapies

i) has a Tregs:Tcons ratio of at least 1:2;

ii) is obtained from T cells that are CD8−, CD9−, and CD25+; and/or

iii) has >70% total cell viability, a negative gram stain, ≥90% CD4+CD25+ cells, and/or ≥50% FoxP3+ cells.

16. The method of claim 13 , wherein the one or more additional therapies is administration of Tregs, and

i) the subject's own Tregs are administered to the subject; and/or

ii) Tregs from the same hematopoietic stem cell donor from which hematopoietic stem cell transplantation was obtained are used.

17. The method of claim 13 , wherein the one or more additional therapies is administration of Tregs and the Tregs are administered

i) as an infusion; and/or

ii) before, concurrently with, or after IL-2 administration.

18. The method of claim 13 , wherein the one or more additional therapies is extra-corporeal photopheresis (ECP).