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Immunological Consequences of Interleukin 12 Administration after Autologous Stem Cell Transplantation

Bone Marrow and Stem Cell Transplantation Program, Lymphoma Program, and the Division of Hematology/Oncology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana

Purpose: The purpose is to determine the immunological effects of recombinant human interleukin (rhIL)-12 therapy after autologous stem cell transplantation.

Experimental Design: Twelve patients (8 non-Hodgkin’s lymphoma, 2 Hodgkin’s disease, and 2 plasma cell myeloma) were treated with rhIL-12 by bolus i.v. injection in doses of 30, 100, or 250 ng/kg starting at a median of 66 days posttransplant. Immunological assays were performed using serum and peripheral blood mononuclear cell (PBMC) samples obtained on study.

Results: Dose-dependent increases in the total lymphocyte count occurred during rhIL-12 therapy. The absolute number of peripheral blood CD4 T cells increased up to 16.3-fold, CD8 T cells up to 20.5-fold, B cells up to 11-fold, and natural killer (NK) cells up to 12.3-fold during rhIL-12 administration and returned to pretreatment baseline levels after discontinuation of rhIL-12. CD56^bright NK cells expanded dramatically in the blood of a patient with baseline lymphopenia before rhIL-12 therapy. In vitro proliferation of patient PBMCs in response to IL-12 was indistinguishable from that of PBMCs obtained from healthy control sub-jects. Moreover, spontaneous in vitro proliferation of patient PBMCs increased significantly during rhIL-12 therapy. Increased levels of IFN- and IL-18 were detected in the serum of patients treated in the 100 and 250 ng/kg dose cohorts during the first multiple dose cycle.

Conclusions: Expansion of T, B, and NK cells occurs in vivo during rhIL-12 therapy after autologous stem cell transplantation for hematological malignancies. In contrast to their striking defect in IL-12-induced IFN- production, posttransplant patient PBMCs exhibit normal proliferative responses to IL-12 in vitro. Additional investigation of rhIL-12 for posttransplantation immunotherapy is warranted.

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