Brain Stem Gliomas Treated With Adoptive Cellular Therapy During Focal Radiotherapy Recovery Alone or With Dose-intensified Temozolomide (Phase I)

NCT ID: NCT03396575

Last Updated: 2025-10-29

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE1
• Total Enrollment: 11 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2018-07-17
• Study Completion Date: 2025-03-20

Brief Summary

The standard of care for children with DIPG includes focal radiotherapy (RT) but outcomes have remained dismal despite this treatment. The addition of oral Temozolomide (TMZ) concurrently with RT followed by monthly TMZ was also found to be safe but ineffective. Recent studies in adults have shown that certain types of chemotherapy induce a profound but transient lymphopenia (low blood lymphocytes) and vaccinating and/or the adoptive transfer of tumor-specific lymphocytes into the cancer patient during this lymphopenic state leads to dramatic T cell expansion and potent immunologic and clinical responses. Therefore, patients in this study will either receive concurrent TMZ during RT and immunotherapy during and after maintenance cycles of dose-intensive TMZ (Group A) or focal radiotherapy alone and immunotherapy without maintenance DI TMZ (Group B). Immune responses during cycles of DC vaccination with or without DI TMZ will be evaluated in both treatment groups.

Detailed Description

The standard of care for children with DIPG includes external beam focal radiotherapy (RT) but outcomes have remained dismal despite this treatment. The addition of oral Temozolomide (TMZ) concurrently with focal irradiation followed by maintenance monthly TMZ was also found to be safe but ineffective. However, in the context of an immunotherapy strategy, it might be beneficial to use TMZ as an adjuvant therapy during and following radiotherapy. Recent pre-clinical and clinical studies in adults with have shown that both myeloablative (MA) and non-myeloablative (NMA) chemotherapy induce a profound but transient lymphopenia and, somewhat counterintuitively, vaccination during recovery from this lymphopenic state and/or the adoptive transfer of tumor-specific lymphocytes into lymphodepleted hosts leads to dramatic in vivo T cell expansion and potent immunologic and clinical responses. Therefore, the study team expects that tumor-specific lymphocytes, expanded ex vivo with the use of TTRNA-pulsed DCs may provide a source of lymphocytes that preferentially expand in this lymphopenic environment following TMZ, and serve as a source of responder cells to subsequent DC vaccination.

TMZ induces profound lymphopenia in children with central nervous system (CNS) tumors. It has not been conclusively shown to help in augmenting vaccine-induced immune responses in this population. Patients in this study will either receive concurrent TMZ during RT and immunotherapy during and after maintenance cycles of dose-intensive TMZ (Group A) or focal radiotherapy alone and immunotherapy without maintenance DI TMZ (Group B). Immune responses during cycles of DC vaccination with or without DI TMZ will be evaluated in both treatment groups. The immunotherapy regimen will consist of TTRNA-DC vaccines alone followed by adoptive cellular therapy consisting of ex vivo expanded tumor-reactive lymphocytes coupled with TTRNA-DC vaccines and autologous HSCs.

Patients in Group B will not receive DI TMZ, however, they will receive lymphodepletion with cyclophosphamide + fludarabine after DC vaccination and prior to the intravenous infusion of ex vivo expanded tumor-reactive lymphocytes. T cell engraftment and persistence has been shown to be augmented by lymphodepletion in numerous studies. TTRNA-pulsed DCs will be given in conjunction with the adjuvants GM-CSF and tetanus-diphtheria toxoid (Td) vaccine which the study team have shown can significantly enhance clinical responses to DC vaccination.

Conditions

Diffuse Intrinsic Pontine Glioma (DIPG); Brain Stem Glioma

Study Design

• Allocation Method: NON_RANDOMIZED
• Intervention Model: SEQUENTIAL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: NONE

Study Groups

Group A

TTRNA-DC vaccines with GM-CSF and TTRNA-xALT plus Td vaccine with Autologous Hematopoietic Stem cells (HSCs) during cycles of Dose-intensified TMZ

Group Type: EXPERIMENTAL

TTRNA-DC vaccines with GM-CSF

Intervention Type: BIOLOGICAL

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.

TTRNA-xALT

Intervention Type: BIOLOGICAL

During TMZ Cycle 4 and with DC vaccine #6, an infusion of T-cells will be administered to all subjects.

Dose-Intensified TMZ

Intervention Type: DRUG

After chemoradiation, subjects in Group A 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.

Td vaccine

Intervention Type: DRUG

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.

Autologous Hematopoietic Stem Cells (HSC)

Intervention Type: BIOLOGICAL

During Cycle 4, all patients will receive HSCs prior to xALT infusion and DC vaccine #6.

Group B

TTRNA-DC vaccines with GM-CSF and TTRNA-xALT plus Td vaccine with Autologous Hematopoietic Stem cells (HSCs) with Cyclophosphamide + Fludarabine Lymphodepletive Conditioning

Group Type: EXPERIMENTAL

TTRNA-DC vaccines with GM-CSF

Intervention Type: BIOLOGICAL

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.

TTRNA-xALT

Intervention Type: BIOLOGICAL

During TMZ Cycle 4 and with DC vaccine #6, an infusion of T-cells will be administered to all subjects.

Cyclophosphamide + Fludarabine Lymphodepletive Conditioning

Intervention Type: DRUG

Subjects in Group B, however, will receive lymphodepletion with cyclophosphamide + fludarabine after DC vaccination and prior to the intravenous infusion of ex vivo expanded tumor-reactive lymphocytes.

Td vaccine

Intervention Type: DRUG

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.

Autologous Hematopoietic Stem Cells (HSC)

Intervention Type: BIOLOGICAL

During Cycle 4, all patients will receive HSCs prior to xALT infusion and DC vaccine #6.

Interventions

TTRNA-DC vaccines with GM-CSF

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.

Intervention Type: BIOLOGICAL

TTRNA-xALT

During TMZ Cycle 4 and with DC vaccine #6, an infusion of T-cells will be administered to all subjects.

Intervention Type: BIOLOGICAL

Cyclophosphamide + Fludarabine Lymphodepletive Conditioning

Subjects in Group B, however, will receive lymphodepletion with cyclophosphamide + fludarabine after DC vaccination and prior to the intravenous infusion of ex vivo expanded tumor-reactive lymphocytes.

Intervention Type: DRUG

Dose-Intensified TMZ

After chemoradiation, subjects in Group A 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.

Intervention Type: DRUG

Td vaccine

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.

Intervention Type: DRUG

Autologous Hematopoietic Stem Cells (HSC)

During Cycle 4, all patients will receive HSCs prior to xALT infusion and DC vaccine #6.

Intervention Type: BIOLOGICAL

Eligibility Criteria

Inclusion Criteria

Initial Screening

• Radiologically confirmed DIPG or other diffuse intrinsic brain stem glioma (Grade III or IV).
• Patient and/or parents/guardian willing to consent to biopsy for obtaining tumor material for confirmatory diagnosis and/or tumor RNA extraction and amplification.
• Biopsy confirmation of any grade of glioma (for patients with classic DIPG on neuroimaging or at least grade III glioma in case of other diffuse intrinsic brain stem gliomas)
• Karnofsky Performance Status (KPS) of > 50% (KPS for > 16 years of age) or Lansky performance Score (LPS) of ≥ 50 (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)
• Hemoglobin > 8 g/dL (can be transfused)
• 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
• Patients of childbearing or child-fathering potential must be willing to use medically acceptable forms of birth control while being treated on this study.
• Signed informed consent according to institutional guidelines.

Post Biopsy

• Patients with post-surgical neurological deficits should have deficits that are stable for a minimum of 1 week prior to registration;
• Pathologic diagnosis of glioma on tumor biopsy.

Exclusion Criteria

• Patients with severe dysphagia, obtundation, or tetraplegia (poor risks for anesthesia and biopsy procedure);
• Absence of tumor on biopsy specimen;
• 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;
• Patients with significant renal, cardiac, pulmonary, hepatic or other organ dysfunction;
• Severe or unstable concurrent medical conditions;
• Patients who require corticosteroids above physiologic doses (>4 mg/day dexamethasone) after chemoradiotherapy;
• Patients scheduled to receive any other concurrent anticancer or investigational drug therapy;
• Prior allergic reaction to TMZ, GM-CSF, or Td;
• Patients who are unwilling or unable to receive treatment and undergo follow-up evaluations at University of Florida;
• Patient and/or parent/guardian demonstrating an inability to comply with the study and/or follow-up procedures.

• Minimum Eligible Age: 3 Years
• Maximum Eligible Age: 30 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Accelerate Brain Cancer Cure

OTHER

Sponsor Role: collaborator

Lyla Nsouli Foundation

UNKNOWN

Sponsor Role: collaborator

University of Florida

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Elias Sayour, MD, PhD

Role: PRINCIPAL_INVESTIGATOR

University of Florida

Locations

UF Health Shands Children's Hospital

Gainesville, Florida, United States

Countries

United States

Other Identifiers

OCR16024

Identifier Type: OTHER

Identifier Source: secondary_id

IRB201701296

Identifier Type: -

Identifier Source: org_study_id