ABSTRACT
PURPOSE: Ganglioside G(D2) is strongly expressed on the surface of human neuroblastoma cells. It has been shown that the chimeric human/murine anti-G(D2) monoclonal antibody (ch14.18) can induce lysis of neuroblastoma cells by antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity. The purposes of the study were (1) to determine the maximum-tolerated dose (MTD) of ch14.18 in combination with standard dose granulocyte-macrophage colony-stimulating factor (GM-CSF) for patients with neuroblastoma who recently completed hematopoietic stem-cell transplantation (HSCT), and (2) to determine the toxicities of ch14.18 with GM-CSF in this setting. PATIENTS AND METHODS: Patients became eligible when the total absolute phagocyte count (APC) was greater than 1, 000/microL after HSCT. ch14.18 was infused intravenously over 5 hours daily for 4 consecutive days. Patients received GM-CSF 250 microg/m(2)/d starting at least 3 days before ch14.18 and continued for 3 days after the completion of ch14.18. The ch14.18 dose levels were 20, 30, 40, and 50 mg/m(2)/d. In the absence of progressive disease, patients were allowed to receive up to six 4-day courses of ch14.18 therapy with GM-CSF. Nineteen patients with neuroblastoma were treated. RESULTS: A total of 79 courses were administered. No toxic deaths occurred. The main toxicities were severe neuropathic pain, fever, nausea/vomiting, urticaria, hypotension, mild to moderate capillary leak syndrome, and neurotoxicity. Three dose-limiting toxicities were observed among six patients at 50 mg/m(2)/d: intractable neuropathic pain, grade 3 recurrent urticaria, and grade 4 vomiting. Human antichimeric antibody developed in 28% of patients. CONCLUSION: ch14.18 can be administered with GM-CSF after HSCT in patients with neuroblastoma with manageable toxicities. The MTD is 40 mg/m(2)/d for 4 days when given in this schedule with GM-CSF.
Subject(s)
Antibodies, Monoclonal/adverse effects , Gangliosides/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Hematopoietic Stem Cell Transplantation , Neuroblastoma/therapy , Adolescent , Animals , Antibodies, Monoclonal/administration & dosage , Antibodies, Monoclonal/blood , Antibodies, Monoclonal/immunology , Antibody Formation/immunology , Antibody-Dependent Cell Cytotoxicity , Child , Child, Preschool , Combined Modality Therapy , Disease Progression , Dose-Response Relationship, Immunologic , Drug Administration Schedule , Female , Follow-Up Studies , Humans , Male , Mice , Neuroblastoma/immunology , Recombinant Fusion Proteins/administration & dosage , Recombinant Fusion Proteins/adverse effects , Recombinant Fusion Proteins/immunologyABSTRACT
Lymphocytes from patients receiving in vivo interleukin (IL)-2 therapy possess enhanced in vitro proliferative and cytotoxic responses to IL-2. The cells from these patients that respond to exogenous IL-2 are CD56+ natural killer cells expressing intermediate-affinity IL-2 receptor betagamma(c) complexes. Because IL-15 activates cells via these same betagamma(c) receptors, we hypothesized that IL-15 would also activate lymphocytes from patients treated with in vivo IL-2 therapy and therefore that IL-15 might potentially be useful as an immunotherapeutic agent alone or in combination with IL-2. We report here that peripheral blood mononuclear cells (PBMCs) from patients receiving in vivo IL-2 therapy do proliferate in response to IL-15. However, a greater dose of IL-15 is needed to reach the same level of proliferation stimulated by IL-2. The EC50 for IL-2 is 0.21 +/- 0.04 nM (mean +/- SE; n = 18), whereas the EC50 for IL-15-stimulated proliferation is 1.16 +/- 0.16 nM (n = 18). In contrast to the proliferative response, equivalent doses of IL-2 and IL-15 stimulate patient PBMCs to mediate similar levels of cytotoxicity against Daudi, K562, and LA-N-5 tumor targets. Notably, low concentrations of IL-15 that do not stimulate a substantial proliferative response (e.g., 1.0 ng/ml) do boost PBMCs to mediate cytotoxicity against these tumor targets. These distinct dose-response curves for proliferation compared to cytotoxicity suggest that IL-15 should be evaluated for its potential as an immunotherapeutic agent to treat cancer, particularly in regimens providing doses that might minimize the proliferative response (associated with cytokine release and toxic side effects) while maintaining the cytolytic antitumor response.
