Adoptive Cellular Therapy in Pediatric Patients With High-grade Gliomas

Study Overview
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Brief Summary
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It is believed that the body's immune system protects the body by attacking and killing tumor cells. T-lymphocytes (T-cells) are part of the immune system and can attack when they recognize special proteins on the surface of tumors. In most patients with advanced cancer, T-cells are not stimulated enough to kill the tumor. In this research study, we will use a patient's tumor to make a vaccine which we hope will stimulate T-cells to kill tumor cells and leave normal cells alone. High grade gliomas (HGGs) are very aggressive and difficult for the body's immune system to attack. Before T-cells can become active against tumor cells, they require strong stimulation by special stimulator cells in the body called Dendritic Cells (DCs) which are also part of the immune system. DCs can recognize the cancer cells and then activate the T lymphocytes, and create this strong stimulation. The purpose of this research study is to learn whether anti-tumor T-cells and anti-tumor DC vaccines can be given safely. Most importantly, this study is also to determine whether the T-cells and DC vaccines can stimulate a person's immune system to fight off the tumor cells in the brain.

Detailed Description
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It is believed that the body's immune system protects the body by attacking and killing tumor cells. T-lymphocytes (T-cells) are part of the immune system and can attack when they recognize special proteins on the surface of tumors. But in most patients with advanced cancer, T-cells are not stimulated enough to kill the tumor. In this research study, we will use your tumor to make a vaccine which we hope will stimulate your T-cells to kill tumor cells and leave your normal cells alone. High grade gliomas (HGGs) are very aggressive and difficult for the body's immune system to attack. Before T-cells can become active against tumor cells, they require strong stimulation by special stimulator cells in the body called Dendritic Cells (DCs) which are also part of the immune system. DCs can recognize the cancer cells and then activate the T lymphocytes, and create this strong stimulation. The purpose of this research study is to learn whether anti-tumor T-cells and anti-tumor DC vaccines can be given safely. Most importantly, this study is also to determine whether the T-cells and DC vaccines can stimulate your immune system to fight off the tumor cells in your brain. When the vaccine for this study is made, dendritic cells will be loaded with genetic material called RNA (ribonucleic acid) from your tumor to stimulate the dendritic cells. The vaccine has two components given at different times after chemoradiation and throughout chemotherapy cycles. The first part, the DC vaccine, involves RNA loaded dendritic cells that are given under the skin at several time points in the study and the second part, xALT vaccine, is a single infusion of tumor-specific T cells delivered through one of two peripheral IV catheters that are placed prior to infusion. This vaccine is investigational which means that it is not approved by the US Food and Drug Administration (FDA) and is being tested in research studies. It is hoped that by injecting the DC vaccine into your skin and infusing the T-cells into your blood, your immune system will be activated against the tumor. Once it is activated against the tumor, your immune system may recognize and attack the tumor cells in your brain and not attack normal cells. Use of a vaccine that stimulates your immune system is called immunotherapy.

Official Title
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ACTION Trial: Adoptive Cellular Therapy Following Dose-Intensified Temozolomide in Newly-diagnosed Pediatric High-grade Gliomas (Phase I).

Conditions
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Malignant Glioma, High Grade Glioma

Intervention / Treatment
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* Biological: TTRNA-DC vaccines with GM-CSF
* Drug: Dose-intensified TMZ
* Biological: Autologous Hematopoietic Stem cells (HSCs)
* Biological: TTRNA-xALT
* Drug: Td vaccine


Participation Criteria
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Eligibility Criteria
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Screening Eligibility: Patients with histologically confirmed WHO Grade III or IV malignant glioma Scheduled for definitive surgical resection of suspected HGG (biopsy only subjects are not eligible for this study) Post-Surgical Resection Eligibility Histologically confirmed WHO Grade III or IV malignant glioma Karnofsky Performance Status (KPS) of ≥ 60% (KPS for ≥ 16 years of age) or Lansky performance Score (LPS) of ≥ 60 (LPS for < 16 years of age) assessed within 2 weeks prior to registration Bone Marrow: ANC (Absolute neutrophil count) ≥ 1000/µl (unsupported); Platelets ≥ 100,000/µl (unsupported for at least 3 days); Hemoglobin > 8 g/dL (may be supported) Renal:Serum creatinine ≤ upper limit of institutional normal Hepatic: Bilirubin ≤ 1.5 times upper limit of institutional normal for age. SGPT (ALT) ≤ 3 times upper limit of institutional normal for age. SGOT (AST) ≤ 3 times upper limit of institutional normal for age. Signed informed consent according to institutional guidelines. Patient or patient guardian consent to PBSC harvest following registration. Subjects of childbearing or child-fathering potential must be willing to use medically acceptable forms of birth control while being treated on this study. Subjects with post-surgical neurological deficits should have deficits that are stable for a minimum of 1 week prior to leukapheresis. Exclusion Criteria: Pregnant or need to breast feed during the study period (Negative serum pregnancy test required). Known autoimmune or immunosuppressive disease or human immunodeficiency virus infection. Subjects with significant renal, cardiac (congestive cardiac failure, myocardial infarction, myocarditis), pulmonary, hepatic or other organ dysfunction. Severe or unstable concurrent medical conditions. Prior allergic reaction to TMZ, GM-CSF, or Td Subjects who are unwilling or unable to receive treatment and undergo follow-up evaluations at the enrolled Sunshine Project Consortium treatment site.

Ages Eligible for Study
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Minimum Age: 3 Years
Maximum Age: 21 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A<br>Dose-intensified TMZ with TTRNA-DC vaccines with GM-CSF and TTRNA-xALT plus Td vaccine without Autologous Hematopoietic Stem cells (HSCs) | Biological: TTRNA-DC vaccines with GM-CSF<br>* After chemoradiation subjects will receive the first cycle of dose-intensified TMZ followed by three biweekly TTRNA-DC vaccines with GM-CSF. Monthly DC vaccines will be given during TMZ Cycles 2-5 for Groups A and B and 48-96 hours after completion of TMZ Cycle 6 Day 21 for Group A and 12-36 hours after HSCs for Group B. All subjects will receive an additional two bi-weekly vaccines during Cycle 6 for a total of 10 DC vaccines. All DC vaccines will be embedded with GM-CSF (150 µg per injection) and given intradermal.<br>Drug: Dose-intensified TMZ<br>* After chemoradiation, subjects will receive the first cycle of dose-intensified TMZ followed by three biweekly TTRNA-DC vaccines with GM-CSF. All subjects will have an additional five cycles of dose-intensified TMZ (for a total of 6 Cycles) with concurrent monthly DC vaccinations.<br>Biological: TTRNA-xALT<br>* During TMZ Cycle 6 and with DC vaccine #8, an infusion of T-cells will be administered to all subjects.<br>Drug: Td vaccine<br>* A full Td booster vaccine will be administered IM at Vaccine #1 to all subjects, and vaccine site pretreatment will be administered to all subjects prior to Vaccine#3, #6, and #8.<br>|
| Experimental: Group B<br>Dose-intensified TMZ with TTRNA-DC vaccines with GM-CSF and TTRNA-xALT plus Td vaccine with Autologous Hematopoietic Stem cells (HSCs) | Biological: TTRNA-DC vaccines with GM-CSF<br>* After chemoradiation subjects will receive the first cycle of dose-intensified TMZ followed by three biweekly TTRNA-DC vaccines with GM-CSF. Monthly DC vaccines will be given during TMZ Cycles 2-5 for Groups A and B and 48-96 hours after completion of TMZ Cycle 6 Day 21 for Group A and 12-36 hours after HSCs for Group B. All subjects will receive an additional two bi-weekly vaccines during Cycle 6 for a total of 10 DC vaccines. All DC vaccines will be embedded with GM-CSF (150 µg per injection) and given intradermal.<br>Drug: Dose-intensified TMZ<br>* After chemoradiation, subjects will receive the first cycle of dose-intensified TMZ followed by three biweekly TTRNA-DC vaccines with GM-CSF. All subjects will have an additional five cycles of dose-intensified TMZ (for a total of 6 Cycles) with concurrent monthly DC vaccinations.<br>Biological: Autologous Hematopoietic Stem cells (HSCs)<br>* Prior to chemoradiation, enrolled subjects will undergo a mobilized leukapheresis for collection of PBSCs and PBMCs for generation of DCs. One group will receive recommended dose of > 2 x 106 CD34+ HSCs/kg. Subjects enrolled in Group B will receive HSCs during TMZ Cycle 6 before receiving DC vaccine and T-cell infusion.<br>Biological: TTRNA-xALT<br>* During TMZ Cycle 6 and with DC vaccine #8, an infusion of T-cells will be administered to all subjects.<br>Drug: Td vaccine<br>* A full Td booster vaccine will be administered IM at Vaccine #1 to all subjects, and vaccine site pretreatment will be administered to all subjects prior to Vaccine#3, #6, and #8.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluate safety of TTRNA-DCs and TTRNA-xALT | Number of subjects with immunotherapy-related dose-limiting toxicities including 1) Grade III or greater non-neurologic toxicity; 2) Grade III neurologic toxicity that does not improve to Grade II or better within 5 days; or 3) Grade IV neurologic toxicity. | From first DC Vaccine through 30 days after administration of the last dose of trial drug or subject death | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Determine feasibility of completing treatment | Number of subjects completing treatment | Up to 10 months | 
| Anti-tumor immune responses | Estimate the mean difference and the variation in INF gamma secretion | up to 10 months | 
| Progression-free survival (PFS) | Days of PFS | Up to 8 years | 
| Overall survival (OS) | Days of OS | Up to 8 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Immunotherapy, Pediatric, Vaccine Therapy, Young adult, Immune system, Dendritic Cell