A Pilot Study of Autologous T-Cell Transplantation With Vaccine Driven Expansion of Anti-Tumor Effectors After Cytoreductive Therapy in Metastatic Pediatric Sarcomas

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

42 participants

Study Classification

INTERVENTIONAL

Study Start Date

1996-12-31

Study Completion Date

2008-09-30

Brief Summary

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This is a single arm study.

The tumor specimen is analyzed for the presence of a fusion protein which corresponds to available peptides. Patients undergo T cell harvest 10 days after an initial priming peptide-pulsed antigen presenting cell (APC) vaccine is performed.

Fresh APCs are utilized for initial priming vaccination. All subsequent vaccinations will use cryopreserved APCs. Minimum number of APCs administered per vaccination is 100,000/kg and maximum is 100,000,000/kg.

Patients undergo cytoreductive therapy for the treatment of their particular malignancy. This therapy usually consists of multiagent chemotherapy in the context of a separate protocol.

Following chemotherapy, infusion of harvested T cells followed by infusion of peptide-pulsed APC vaccinations occurs every 6 weeks for a total of 3 post-priming vaccinations. Influenza vaccine is administered by intramuscular injection concurrent to peptide-pulsed APC vaccines.

Interleukin -2 (IL-2) is administered as a continuous intravenous (IV) infusion for 4 days/week for 3 successive weeks starting on the same day as T cell /peptide-pulsed infusions.

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Detailed Description

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Eradication of low tumor burdens can occur in vivo when T-cell mediated responses are generated against specific tumor antigens. The Ewing's sarcoma family of tumors (ESFT) and alveolar rhabdomyosarcoma (AR) display several features which make them candidate diseases for trials of such immunotherapy. First, intensive cytotoxic chemotherapy is generally able to eradicate bulk disease in patients with metastatic disease, but tumor relapse eventually occurs in nearly all patients. Second, tumor-specific chromosomal translocations resulting in the production of novel fusion proteins have been identified in the great majority of these tumors. Peptides derived from these fusion proteins have been shown to function as tumor antigens for cytolytic T cells in animal studies. Third, studies of immune reconstitution after intensive cytotoxic therapy have provided evidence that antigen-specific T cells can be generated in vivo when the adoptive transfer of peripheral T cells and antigen are provided during the period of T cell regeneration. This process can be augmented in murine models by the use of human immunodeficiency virus (HIV) active protease inhibitor, indinavir, potentially through inhibition of programmed cell death in expanding T cells. Merging these concepts, this protocol will attempt to eradicate minimal residual disease in pediatric patients with metastatic ESFT and AR via vaccination with tumor-specific peptides undertaken concomitant with autologous T cell transplantation and indinavir.

Conditions

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Ewing's Sarcoma Rhabdomyosarcoma

Study Design

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Allocation Method

NA

Intervention Model

SINGLE_GROUP

Primary Study Purpose

TREATMENT

Blinding Strategy

NONE

Study Groups

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Peptide vaccine/autologous T cell transplant/indinavir therapy

Patients receive oral indinavir sulfate 350 mg/m\^2 administered every 8 hours; maximum dose i.e. 800 mg every 8 hours; peptide pulsed dendritic cells 1 x 10\^6 injection; harvested autologous T cells (minimum dose 1 x 10\^6/kg will be thawed rapidly in 37 degree water bath and infused sequentially over 5-15 minutes.

Group Type EXPERIMENTAL

therapeutic autologous dendritic cells

Intervention Type BIOLOGICAL

3 syringes containing 1 x 10\^6peptide pulsed dendritic cells

indinavir sulfate

Intervention Type DRUG

Oral dose, 350 mg/m\^2 administered every 8 hours. Maximum dose is 800 mg every 8 hours.

peripheral blood stem cell transplantation

Intervention Type PROCEDURE

Harvested autologous T cells, minimum dose 1 x 10\^6/kg will be thawed rapidly in 37 degree water bath and infused sequentially over 5-15 minutes.

Interventions

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therapeutic autologous dendritic cells

3 syringes containing 1 x 10\^6peptide pulsed dendritic cells

Intervention Type BIOLOGICAL

indinavir sulfate

Oral dose, 350 mg/m\^2 administered every 8 hours. Maximum dose is 800 mg every 8 hours.

Intervention Type DRUG

peripheral blood stem cell transplantation

Harvested autologous T cells, minimum dose 1 x 10\^6/kg will be thawed rapidly in 37 degree water bath and infused sequentially over 5-15 minutes.

Intervention Type PROCEDURE

Other Intervention Names

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Crixivan

Eligibility Criteria

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Inclusion Criteria

Patients with fusion protein bearing, metastatic malignancies of the following histologic subtypes are eligible for evaluation for treatment on this protocol: alveolar rhabdomyosarcoma (AR), and Ewing's sarcoma family of tumors (ESFT) which includes classical, atypical and extraosseous Ewing's sarcoma, peripheral primitive neuroectodermal tumors, peripheral neuroepithelioma, primitive sarcoma of bone, and ectomesenchymoma. Eligibility will not be confirmed until the presence of a tumor-specific fusion protein is documented by reverse transcription polymerase chain reaction (RT-PCR) which corresponds to one of the tumor-specific peptides available for vaccination.

Patients with Stage IV or metastatic disease are eligible to be enrolled on study at the time of initial presentation with tumor, prior to any cytoreductive therapy.

Alternatively, patients who have recurrent disease, but who have been remotely treated (completed all antineoplastic therapy greater than or equal to one year prior to enrollment for patients who are greater than 5 years of age, or completed all antineoplastic therapy greater than 6 months prior to enrollment for patients who are less than or equal to 5 years of age), are also eligible for enrollment prior to any subsequent cytoreductive therapy.

Patients who have received cytoreductive therapy for Stage IV or metastatic disease may be enrolled at the time of completion of cytoreductive therapy if an apheresis specimen is available which was collected and processed prior to cytotoxic therapy according to the guidelines described in the protocol Section 3.2.2.

Such products will have been obtained by apheresis at the Clinical Center, National Institutes of Health (NIH), with informed consent administered as per protocol 98-C-37, 97-C-0050 or as described on standard government request form 2626 for invasive procedures.

Patients must be less than or equal to 35 years at the time of initial diagnosis of alveolar rhabdomyosarcoma or ESFT, weight greater than 10 kg at the time of apheresis. Patients between 10-15 kg must be approved by the apheresis unit in the Department of Transfusion Medicine (DTM) prior to enrollment on the protocol.

All patients or their legal guardians must give written informed consent indicating their understanding of the investigational nature and risks of the study.

Patients must have adequate renal function (serum creatinine (Cr) less than 1.5 mg/dl or creatinine clearance (Cr Cl), greater than 60 ml/min./1.73 m\^2 and liver function (transaminases less than 3 times normal, bilirubin less than 2.0 mg/dl). Patients will not be excluded based upon abnormal hepatic function which is related to hepatic involvement by tumor.

For remotely treated patients, a CD4 count of greater than or equal to 400 cells/mm\^3 is required.

Exclusion Criteria

Women who are pregnant or lactating.

Patients with human immunodeficiency virus infection due to confounding effects on immune function.

Patients with hepatitis B or hepatitis C infection will be excluded due to the untoward risks to personnel working with blood specimens.

Patients who require daily oral corticosteroid therapy for any underlying disease will be excluded.

Topical or inhaled corticosteroids are permitted.

Patients who are allergic to eggs, egg products, or thimerosal, or have a history of Guillain-Barre syndrome may be enrolled on study but are ineligible to receive the influenza vaccine.

Minimum Eligible Age

5 Years

Maximum Eligible Age

35 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No