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Induction Is Associated with Clinical Response1
Beth Israel Deaconess Medical Center, Division of Hematology/Oncology, Boston, Massachusetts 02215
The
aim of this study was to examine the tolerability, antitumor activity,
and biological effects of a new schedule of i.v. recombinant human
interleukin 12 (rhIL-12). Twenty-eight patients were enrolled in a
Phase I trial in which rhIL-12 was administered twice weekly as an i.v.
bolus for 6 weeks. Stable or responding patients were eligible to
receive additional 6-week cycles until there was no evidence of disease
or until tumor progression. Patient cohorts were treated with
escalating doses of rhIL-12 (30–700 ng/kg). The maximum tolerated dose
(MTD) was 500 ng/kg, with dose-limiting toxicities consisting of
elevated hepatic transaminases and cytopenias. At the MTD
(n = 14), there was one partial response
occurring after 6 cycles of rhIL-12 in a patient with renal cell
cancer. Two additional renal cell cancer patients treated at the MTD
had prolonged disease stabilization, with one of these exhibiting tumor
regression after 8 cycles of rhIL-12. IFN-
, IL-15, and IL-18 were
induced in patients treated with rhIL-12. Whereas IFN- and IL-15
induction were attenuated midway through the first cycle in patients
with disease progression, those patients with tumor regression or
prolonged disease stabilization were able to maintain IFN-, IL-15,
and IL-18 induction. The down-modulation of IFN- induction during
rhIL-12 treatment did not relate to IL-10 production or alterations in
rhIL-12 bioavailability but was associated with an acquired defect in
lymphocyte IFN- production in response to IL-12, IL-2, or IL-15.
This defect could be partially overcome in vitro through
combined stimulation with IL-12 plus IL-2. These findings show that the
chronic administration of twice-weekly i.v. rhIL-12 is well-tolerated,
stimulates the production of IL-12 costimulatory cytokines and IFN-,
and can induce delayed tumor regression. Strategies aimed at
maintaining IFN- induction, such as the addition of IL-2, may
further augment the response rate to this schedule of rhIL-12.
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