A phase I study of 90yttrium-ibritumomab-tiuxetan in children and adolescents with relapsed/refractory CD20-positive non-Hodgkin's lymphoma: a Children's Oncology Group study.

PURPOSE: The prognosis for children with recurrent CD20+ non-Hodgkin's lymphoma is dismal. A radiolabeled anti-CD20 antibody, 90yttrium-ibritumomab-tiuxetan (90Y-IT), is Food and Drug Administration approved for adults with recurrent indolent CD20+ B cell-non-Hodgkin's lymphoma. There is no data on the safety and feasibility of 90Y-IT in refractory childhood CD20+ lymphoma. EXPERIMENTAL DESIGN: Children and adolescents with refractory/relapsed CD20+ lymphoma were eligible for this phase I radioimmunotherapy study. Patients (n=5) received rituximab (250 mg/m2 i.v.) on days 0 and 7 and indium-111 ibritumomab-tiuxetan (5 mCi i.v.) on day 0. Dosimetry studies were done on days 0, 1, 3, and 6. Immediately after rituximab on day 7, patients received 90Y-IT if dosimetry studies showed<2000 cGy exposure to all solid organs and<300 cGy to marrow, as well as 0.4 mCi/kg in patients with good marrow reserve (n=3) and 0.1 mCi/kg in patients with poor marrow reserve (after bone marrow transplant; n=2). RESULTS: No patients experienced nonhematologic or hematologic dose-limiting toxicity. Human antimurine antibody/human antichimeric antibody incidence was 0%. One patient experienced grade II infusion-related chills associated with rituximab. The following are the means of organ radiation exposure (cGy): kidneys 341 (112-515), liver 345 (83-798), lungs 309 (155-519), marrow 46 (20-78), spleen 565 (161-816), and total body 42 (14-68). CONCLUSIONS: Based on these findings, an expanded investigator-initiated limited institutional phase II study has been designed to further evaluate the safety, tolerability, and response rate with 90Y-IT dose stratification based on marrow reserve.

Suppressor function of umbilical cord blood-derived CD4+CD25+ T-regulatory cells exposed to graft-versus-host disease drugs.

BACKGROUND: This study examines the effects of the most commonly used graft-versus-host disease (GVHD) prophylactic drugs on inducing apoptosis and suppressor cell function of human umbilical cord blood (UCB) CD4+25+ Treg and CD4+25- cells. METHODS: Cyclosporin A (CSA), methylprednisolone (MP), methotrexate (MTX), and mycophenolic acid (MPA) were added to the final 6 days of expansion cultures of Treg or CD4+25- T-cells isolated from the same donor and each concurrently cultured under the same conditions. Cell viability was measured for CD4+25+ as compared to CD4+25- T-cells and Treg function was assessed. The effects of these immunosuppressive drugs, Treg cells, or both also were tested in a primary allogeneic mixed lymphocyte response (MLR) response. RESULTS: The cell viability percentages were lower for CD4+25- cells than for Treg cells when MP, MTX, or MPA was added for the last 6 days of an expansion culture. Under these interleukin (IL)-2 based expansion conditions, CSA had no effect. The addition of any of the four GVHD prophylactic agents to the expansion phase of culture did not reduce the MLR suppressive capacity of Treg cells. Overall MLR suppression was increased when Treg cells were added along with CSA and MP to a primary MLR culture, whereas MTX modestly reduced Treg suppression. CONCLUSION: These data indicate a general resistance of expanded UCB Treg cells to GVHD immune suppressive agents and support trials to test UCB Treg infusions under the cover of GVHD prophylactic drugs in hematopoietic cell transplantation.

Trastuzumab and interleukin-2 in HER2-positive metastatic breast cancer: a pilot study.

PURPOSE: Trastuzumab as a single agent has activity in metastatic breast cancer; however, the mechanism of action for this clinical activity is uncertain. Whereas interruption of erbB family member signaling occurs, trastuzumab also mediates antibody-dependent cellular cytotoxicity in vitro and in vivo. Based on these data, a clinical trial was performed to test whether interleukin (IL)-2, by increasing FcRgammaIII(+) natural killer (NK) cell numbers and cytolytic function in vivo, when added to trastuzumab, can increase efficacy, be safely given, and avoid the use of chemotherapy. EXPERIMENTAL DESIGN: In this Phase I trial, 10 patients with HER2-overexpressing metastatic breast cancer were treated with IL-2 (1.75 x 10(6) IU/m(2)/day, s.c.) for 7 weeks and trastuzumab (4 mg/kg load and then 2 mg/kg weekly) for 6 weeks. Safety, in vitro immune responses, and clinical responses were assessed. RESULTS: Ten women received a total of 12 cycles of therapy (each cycle lasted 7 weeks). No significant toxicities were seen, and one patient required an IL-2 dose reduction. Among the evaluable patients (10 cycles), the responses were one partial response, five cases of stable disease, and four cases of progressive disease. In vitro immune assays showed NK cell expansion and trastuzumab-mediated increased NK cell killing of breast cancer targets (antibody-dependent cellular cytotoxicity) in a HER2-specific manner but did not correlate with clinical responses. CONCLUSIONS: Trastuzumab + IL-2 is a well-tolerated outpatient regimen that results in NK cell expansion with enhanced in vitro targeted killing of HER2-expressing cells. These preliminary data suggest that this strategy may benefit heavily pretreated metastatic breast cancer patients.