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

Phase 2

Completed

• Conditions: Ewing's Sarcoma; Rhabdomyosarcoma
• Interventions: Biological: therapeutic autologous dendritic cells; Drug: indinavir sulfate; Procedure: peripheral blood stem cell transplantation

• Registration Number: NCT00001566
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

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.

Detailed Description

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.

Study Timeline

• Study Start: 1996-12
• Study First Submitted: 1999-11-03
• Study First Submitted QC: 1999-11-03
• Study First Posted: 1999-11-04
• Primary Completion: 2008-09
• Study Completion: 2008-09
• Results First Submitted: 2012-03-28
• Results First Submitted QC: 2012-05-08
• Status Verified: 2012-06
• Results First Posted: 2012-06-12
• Last Update Submitted: 2012-06-12
• Last Update Posted: 2012-06-15

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 42

Inclusion Criteria

Not provided

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Peptide vaccine/autologous T cell transplant/indinavir therapy	therapeutic autologous dendritic cells	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.
Peptide vaccine/autologous T cell transplant/indinavir therapy	indinavir sulfate	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.
Peptide vaccine/autologous T cell transplant/indinavir therapy	peripheral blood stem cell transplantation	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.

Primary Outcome Measures

Name	Time	Method
Number of Participants With an Immune Response to Tumor-specific and Non-tumor Specific Peptides During a Period of Immune Reconstitution	20 weeks post vaccination	Immune response was defined as a percent specific lysis of \>10% following challenge with peptide pulsed targets, or interferon gamma production following challenge with peptide pulsed targets \>2-fold that found with no-peptide controls or a proliferation index \>3.0. Tumor specific peptides: Ewings sarcoma Type 1: EF-1 (EWS/FLI-1)\*SSSYGQQN/PSYDSVRRGA,Ewing's Sarcoma Type 2: EF-2 (EWS/FLI-2)\* SSSYGQ/QSSLLAYNT, Alveolar rhabdomyosarcoma: PXFK (PAX3/FKHR)† TIGNGLSPQ/NSIRHNLSL. Non-tumor specific peptide:HPV16E7 MLDLQPETT-MET-9-THR. See protocol link module for additional information re: peptides.
Number of Participants With an Immune Response to Non-Tumor-specific Peptide E7	5 years	Immune response was defined as a percent specific lysis of \>10% following challenge with peptide pulsed targets, or interferon gamma production following challenge with peptide pulsed targets \>2-fold that found with no-peptide controls or a proliferation index \>3.0.
The Percent of Patients Who Recover CD4 Counts Within 6 Months of Completion of Chemotherapy	2 to 6 months	CD4 counts were measured from peripheral blood using standard flow cytometric techniques at the following timepoints: 2 months post-chemotherapy, 4 months post-chemotherapy and 6 months post-chemotherapy. To be eligible for evaluation for this endpoint, patient much have been \<10 years of age and sustained a CD4 count of \<300 cells/mcl upon completion of standard therapy. Recovery was defined as a CD4 count \> 500 cells/mcl at any timepoint within 6 months of completing chemotherapy.
Number of Participants With an Immune Response to the Translocation Breakpoint Peptide	5 years	Immune responses were measured following 3 sequential influenza vaccines during the same period as the peptide-pulsed dendritic cell vaccines.
Number of Participants With an Immune Response to Tumor-Specific Peptides at the Time of Presentation	Once per enrollment	Immune response was defined as a percent specific lysis of \>10% following challenge with tumor peptide pulsed targets, or interferon gamma production following challenge with tumor peptide pulsed targets \>2-fold that found with no-peptide controls or a proliferation index \>3.0 to tumor peptide targets.Tumor specific peptides: Ewings sarcoma Type 1: EF-1 (EWS/FLI-1)\*SSSYGQQN/PSYDSVRRGA,Ewing's Sarcoma Type 2: EF-2 (EWS/FLI-2)\* SSSYGQ/QSSLLAYNT, Alveolar rhabdomyosarcoma: PXFK (PAX3/FKHR)† TIGNGLSPQ/NSIRHNLSL. See protocol link module for additional information re: peptides.

Secondary Outcome Measures

Name	Time	Method
Percent of Participants: Event Free Survival	5 years	Event free survival is calculated from the date of diagnosis for patients enrolled with newly diagnosed metastatic disease and from the date of the last recurrence detection before enrollment on this study for patients with recurrent disease.
Number of Participants With Adverse Events	5 years	Here are the number of participants with adverse events. For the detailed list of adverse events see the adverse event module.
Median Overall Survival	5.4 years	Overall survival is defined as the time between the first day of treatment to the day of death.
Percentage of Participants Overall Survival	5 years	Overall survival is defined as the time between the first day of treatment to the day of death.

Trial Locations

Locations (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike; 🇺🇸 Bethesda, Maryland, United States