Clinical and immunological effects of granulocyte-macrophage colony-stimulating factor coadministered with interleukin 2: a phase IB study
Interleukin 2 (IL-2) and granulocytes-macrophage colony-stimulating factor (GM-CSF) are activators of the lymphocyte and granulocyte/macrophage series, respectively. We conducted a phase IB trial to identify the maximally tolerated dose and to assess immunological effects of the combination. Thirty-...
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Veröffentlicht in: | Clinical cancer research 1996-02, Vol.2 (2), p.319-330 |
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Zusammenfassung: | Interleukin 2 (IL-2) and granulocytes-macrophage colony-stimulating factor (GM-CSF) are activators of the lymphocyte and granulocyte/macrophage
series, respectively. We conducted a phase IB trial to identify the maximally tolerated dose and to assess immunological effects
of the combination. Thirty-four patients with incurable cancers received 2.5, 5, or 10 microgram/kg GM-CSF s.c. either before
or concurrently with 1.5 or 3.0 million units/m2/day IL-2. The most common laboratory and clinical side effects included an
elevation of the total WBC or eosinophil count due to GM-CSF, and constitutional symptoms due to IL-2. Grade 3 or 4 toxicities
included hypotension, thrombocytopenia, elevations in aspartate aminotransferase or bilirubin, renal toxicity, gastrointestinal
hemorrhage, arrhythmia, and constitutional symptoms. Two patients receiving 5.0 microgram/kg GM-CSF plus concurrent 3.0 million
units IL-2 experienced dose-limiting grade 3 or 4 neurological toxicity, which reversed almost completely. An increase in
the serum-soluble IL-2 alpha chain receptor was observed with administration of GM-CSF, IL-2, or the combination. IL-2 therapy
enhanced lymphokine-activated killer activity, antibody-dependent cellular cytotoxicity, and lymphocyte activation, with increased
CD16 and CD56 expression. GM-CSF increased expression of human leukocyte antigen DR on peripheral blood monocytes and decreased
surface expression of CD16 on circulating monocytes and polymorphonuclear cells. Lymphokine-activated killer activity and
CD16 expression on monocytes and lymphocytes and CD56 expression on lymphocytes were significantly lower in patients receiving
GM-CSF simultaneously with IL-2 than in patients receiving the sequential treatment. Antitumor activity was observed in the
lungs of four of eight renal cell carcinoma patients with pulmonary metastases treated with concurrent GM-CSF and IL-2. Although
no or minimal shrinkage was observed in the patients' large primary tumors, these results warrant further study. The recommended
initial Phase II dose and schedule is 1.25 microgram/kg/day GM-CSF, given concurrently with 1.5 million Roche units/m2/day
(4.5 x 10(6) international units/m2/day) IL-2, with subsequent escalation of GM-CSF to 2.5 microgram/kg/day after careful
observation for toxicities. |
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ISSN: | 1078-0432 1557-3265 |