RATIONALE: Biological therapies use different ways to stimulate the immune system and stop cancer cell from growing. Inserting genetic material made in the laboratory into a person's blood cells may make the body build an immune response to kill tumor cells. PURPOSE: Phase I trial to study the effectiveness of biological therapy and gene therapy in treating children who have recurrent or refractory neuroblastoma.

Condition	Treatment or Intervention	Phase
disseminated neuroblastoma Drug Toxicity recurrent neuroblastoma	Procedure: chemotherapy  Procedure: biological response modifier therapy  Drug: hematologic toxicity attenuation  Procedure: peripheral blood lymphocyte therapy  Behavior: supportive care/therapy  Procedure: gene therapy  Procedure: cytokine therapy  Procedure: interleukin therapy  Procedure: leukocyte therapy  Drug: autologous lymphocytes  Drug: ganciclovir  Drug: interleukin-2	Phase I

Further Study Details: 

OBJECTIVES: I. Determine the safety and toxicity of cellular immunotherapy using ex vivo expanded autologous CD8+ cytotoxic T-lymphocyte clones genetically modified to express the CE7R scFvFc:zeta chimeric immunoreceptor and the HyTK selection/suicide gene in children with recurrent or refractory disseminated neuroblastoma. II. Determine the antitumor activity of this regimen in these patients. III. Determine the duration of in vivo persistence of adoptively transferred clones and the effect of interleukin-2 on maintaining the in vivo persistence of these clones. IV. Screen for the development of host anti-scFvFc:zeta and HyTK immune responses in patients treated with this regimen. V. Determine the efficacy of ganciclovir in ablating transferred clones in vivo if toxicity occurs in these patients.

PROTOCOL OUTLINE: This is a multicenter study. Patients undergo autologous peripheral blood stem cell harvest. CD8+ cytotoxic T-lymphocyte (CTL) clones are isolated, genetically modified to express the CE7R scFvFc:zeta chimeric immunoreceptor and the HyTK selection/suicide gene, and then expanded ex vivo. While the modified CTL clones are being generated, patients each receive an individualized salvage chemotherapy regimen that may consist of one of the following: cyclophosphamide and topotecan; ifosfamide, carboplatin, and etoposide; or another chemotherapy regimen chosen by the patient's primary oncologist. The first cohort of 5 patients receives escalating doses of modified CTL clones IV over 30 minutes on days 0, 14, and 28 in the absence of disease progression or unacceptable toxicity. Each patient begins the series of 3 infusions as soon as an adequate number of modified CTL clones are ready and after the acute side effects of chemotherapy have resolved. In the absence of unacceptable toxicity in the first cohort, the second cohort of 5 patients receives the same treatment as cohort 1 plus interleukin-2 subcutaneously every 12 hours on days 15-24 and 29-38. Patients with unacceptable toxicity receive ganciclovir IV every 12 hours for 14 days (or longer if symptomatic resolution is not achieved in that interval). Patients are followed at day 100 and then periodically thereafter.

PROJECTED ACCRUAL: A total of 10 patients will be accrued for this study within 3 years.

Ages Eligible for Study:  1 Year   -   17 Years

Criteria

PROTOCOL ENTRY CRITERIA:

--Disease Characteristics--

• Histologically and/or radiographically proven disseminated neuroblastoma; Recurrent or refractory to first-line therapy as defined by less than complete response to standard induction chemotherapy combined with surgical resection
• Histologic verification of neuroblastoma required at original diagnosis
• No radiographically detectable CNS involvement
• No clinically evident progressive encephalopathy

--Prior/Concurrent Therapy--

• Biologic therapy: No other concurrent antibody therapy during or after study; No other concurrent immunotherapy (e.g., interferons, vaccines, or other cellular products)
• Chemotherapy: At least 3 weeks since prior standard or experimental chemotherapy and recovered
• Endocrine therapy: No concurrent systemic corticosteroids unless specifically for amelioration of toxicity induced by transferred T-cell therapy
• Radiotherapy: Not specified
• Surgery: Not specified
• Other: At least 3 weeks since prior immunosuppressive therapies and recovered; No concurrent pentoxifylline; No other concurrent investigational agents; No concurrent ganciclovir, any ganciclovir derivatives, or acyclovir for non-life-threatening herpes virus infections

--Patient Characteristics--

• Age: 1 to 17 (children only)
• Performance status: Not specified
• Life expectancy: At least 3 months
• Hematopoietic: Not specified
• Hepatic: Not specified
• Renal: No dialysis dependency
• Cardiovascular: No uncontrolled cardiac arrhythmia; No hypertension requiring pressor support
• Pulmonary: No requirement for supplemental oxygen unless expected to resolve within 2 weeks
• Neurologic: See Disease Characteristics; No refractory seizure disorder
• Other: No detectable human antimouse antibody reactivity if received prior murine antibody preparations; No history of ganciclovir allergy or intolerance; HIV negative; Not pregnant or nursing; Negative pregnancy test; Fertile patients must use effective contraception during and for at least 2 months after study

California
      Cancer Center and Beckman Research Institute, City of Hope, Duarte,  California,  91010-3000,  United States
Washington
      Fred Hutchinson Cancer Research Center, Seattle,  Washington,  98109-1024,  United States

Study chairs or principal investigators

Julie Park,  Study Chair,  Fred Hutchinson Cancer Research Center   

Study ID Numbers:  CDR0000068310; FHCRC-1524.00; NCI-H00-0065
Record last reviewed:  December 2003
Last Updated:  October 13, 2004
Record first received:  November 6, 2000
ClinicalTrials.gov Identifier:  NCT00006480
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08