Interleukin-12 therapy of cutaneous T-cell lymphoma induces lesion regression and cytotoxic T-cell responses

Progression of cutaneous T-cell lymphoma (CTCL) is associated with profound defects in cell-mediated immunity and depressed production of cytokines, w hich support cell-mediated immunity. Because we have observed marked defect s in interleukin-12 (IL-12) production in CTCL and because IL-12 is critica l for antitumor cytotoxic T-cell responses, we initiated a phase I dose esc alation trial with recombinant human IL-12 (rhlL-12) where patients receive d either 50, 100, or 300 ng/kg rhIL-12 twice weekly subcutaneously or intra lesionally for up to 24 weeks. Ten patients were entered: 5 with extensive plaque, 3 with Sezary syndrome, and 2 with extensive tumors with large cell transformation. One patient with Sezary syndrome dropped out after 1 week for personal reasons. Subcutaneous dosing resulted in complete responses (C R) in 2 of 5 plaque and partial responses (PR) in 2 of 5 plaque, and 1 of 2 Sezary syndrome (overall response rate CR+PR 5 of 9, 56%), A minor respons e also occurred in 1 of 5 plaque patients. Intralesional dosing resulted in individual tumor regression in 2 of 2 patients. Biopsy of regressing lesio ns showed a significant decrease in the density of the infiltrate in all ca ses and complete resolution of the infiltrate among those with clinical les ion resolution. An increase in numbers of CD8-positive and/or TIA-1-positiv e T cells were observed on immunohistochemical analysis of skin biopsy spec imens obtained from regressing skin lesions. Adverse effects of rhIL-12 on this regimen were minor and limited and included low grade fever and headac he. One patient discontinued rhIL-12 at week 6 because of depression. These results suggest that rhIL-12 may augment antitumor cytotoxic T-cell respon ses and may represent a potent and well-tolerated therapeutic agent for CTC L. (C) 1999 by The American Society of Hematology.