Adoptive T Cell Therapy, DC Vaccines, and Hematopoietic Stem Cells Combined With Immune checkPOINT Blockade in Patients With Medulloblastoma
NCT ID: NCT06514898
Last Updated: 2025-12-18
Study Results
The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.
Basic Information
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ACTIVE_NOT_RECRUITING
PHASE1
12 participants
INTERVENTIONAL
2025-05-05
2028-12-01
Brief Summary
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Detailed Description
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After a screening consent is obtained for the collection of tumor sample, subjects will undergo standard of care resection for tumor debulking or biopsy for confirmatory diagnosis of disease progression. Tumor tissue will be collected during surgery for tumor debulking or biopsy for total tumor RNA and generation of investigational DC vaccine in parallel. Following biopsy and confirmatory pathologic diagnosis of recurrent MB, patients will be enrolled in the treatment phase of the trial after obtaining informed consent.
After surgery, patients will undergo a mobilized pheresis to collect PBMCs for DC generation and CD34+ HSCs. Amplified tumor RNA obtained from surgically resected or biopsied specimens will be used to generate total tumor RNA-pulsed DCs (TTRNA-DCs) manufactured while patients initiate post-surgical salvage chemotherapy regimen.
Salvage chemotherapy prescribed by treating neuro-oncologist will initiate 1-2 weeks after G-CSF mobilized leukapheresis for 1-3 cycles after which, treatment cycles will be paused, and the patients will receive 3 priming TTRNA-DCs vaccines every 2 weeks and undergo a non-mobilized leukapheresis to collect vaccine-boosted lymphocytes for ex vivo T cell expansion and generation of additional TTRNA-DC vaccines. Treatment with salvage chemotherapy will resume with monthly TTRNA-DC vaccines for an additional 1-3 cycles until ex vivo expanded T cells are manufactured and released from the UF cGMP facility.
For ACT, patients will undergo non-myeloablative conditioning with cyclophosphamide/fludarabine followed by infusion of ex vivo expanded tumor-reactive lymphocytes at 3 x 108 cells/Kg, infusion of autologous CD34+ HSCs (targeted dose of 2 x 106 CD34+ HSCs/Kg), PD-1 blockade and three biweekly intradermal TTRNA-DC vaccines to boost T cell engraftment and expansion.
The total immunotherapy regimen will consist of up to 9 intradermal DC vaccines (three -bi-weekly (q2 weeks) for priming, monthly for additional 2-3 cycles during T cell expansion, and three bi-weekly during T cell engraftment), a single intravenous infusion of ex vivo expanded tumor-reactive T cells, and a. single intravenous infusion of autologous HSCs; and PD-1 blockade IV starting with ACT continuing for up to 2 years as long as tolerable and without disease progression.
All patients will receive a full Td booster (5 Lf) IM vaccine 4-24 hours prior to Vaccine #1, regardless of booster history. All patients will undergo vaccine site pretreatment with a one-fifth dose of Td (1 Lf) intradermally, at the site of planned DC vaccine, 4-24 hours prior to vaccines #3, #5, #7 and #9.
Conditions
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Study Design
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NA
SINGLE_GROUP
TREATMENT
NONE
Study Groups
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Adoptive Cellular Therapy (ACT) + PD-1 blockade with pembrolizumab
ACT + PD-1 blockade consists of the intravenous delivery of ex vivo expanded tumor-reactive lymphocytes and autologous hematopoietic stem cells (HSCs) with concomitant tumor RNA-pulsed DC vaccines followed by intravenous delivery of PD-1 blocking antibodies.
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.
up to 9 intradermal DC vaccines (three -bi-weekly (q2 weeks) for priming, monthly for additional 2-3 cycles during T cell expansion, and three bi-weekly during T cell engraftment)
TTRNA-xALT
All participants will receive a single infusion of T-cells.
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, #5, #7 and #9.
autologous HSCs
All participants will receive a single intravenous infusion of autologous HSCs.
Pembrolizumab
Participants will receive PD-1 blockade IV starting with ACT continuing for up to 2 years as long as tolerable and without disease progression.
Interventions
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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.
up to 9 intradermal DC vaccines (three -bi-weekly (q2 weeks) for priming, monthly for additional 2-3 cycles during T cell expansion, and three bi-weekly during T cell engraftment)
TTRNA-xALT
All participants will receive a single infusion of T-cells.
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, #5, #7 and #9.
autologous HSCs
All participants will receive a single intravenous infusion of autologous HSCs.
Pembrolizumab
Participants will receive PD-1 blockade IV starting with ACT continuing for up to 2 years as long as tolerable and without disease progression.
Eligibility Criteria
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Inclusion Criteria
2. Must be a candidate for surgery/biopsy Or tumor tissue obtained clinically, has been previously stored in a biorepository suitable for tumor RNA extraction and amplification and sample is made available to the PI.
3. Karnofsky or Lansky Performance Status (KPS) ≥ 60% (KPS for \> 16 years of age) or Lansky performance Score (LPS) of ≥ 60 (LPS for \< 16 years of age)
4. Adequate bone marrow and organ function as defined below:
* ANC ≥ 1,000/mcL (unsupported)
* Platelets ≥ 100,000/mcL (unsupported for at least 3 days)
* Hemoglobin ≥ 9 g/dL (may be supported)
* Serum creatinine ≤ 1.5 x IULN OR Creatinine clearance by Cockcroft-Gault ≥ 60 mL/min for patients with serum creatinine \> 1.5 x IULN
* Serum total bilirubin ≤ 1.5 x IULN for age OR Direct bilirubin ≤ IULN for patients with total bilirubin \> 1.5 x IULN for age
* AST (SGOT) and ALT (SGPT) ≤ 3 x IULN for age
* Cardiac shortening fraction ≥27% or LVEF ≥50% by echocardiogram
* Adequate pulmonary function defined as baseline pulse oximetry of ≥92% on room air
5. For females of childbearing potential, negative serum pregnancy test at enrollment
6. For women of childbearing potential (WOCBP) must be willing to use acceptable contraceptive methods to avoid pregnancy throughout the study and for at least 24 weeks after the last dose of study drug.
or For males with female partners of childbearing potential must agree to use physician-approved contraceptive methods (e.g., abstinence, condoms, vasectomy) throughout the study and should avoid conceiving children for 24 weeks following the last dose of study drug.
7. Signed informed consent by patient and/or legally authorized representative
Exclusion Criteria
1. Prior discontinuation of PD-1 inhibitor treatment due to toxicity or disease progression.
2. Corticosteroids equivalent to ≥ 4mg dexamethasone daily.
3. HIV, Hepatitis B, or Hepatitis C seropositive.
4. Known active infection or immunosuppressive disease.
5. Autoimmune disease requiring medical management with immunosuppressant.
6. Pregnancy or lactation, due to possible adverse effects on the developing fetus or infant.
7. Treatment with another investigational drug or other intervention within 30 days prior to projected first dose of study treatment (Priming phase with TTRNA-DC).
8. Severe, active co-morbidity, defined as follows:
* Unstable angina and/or congestive heart failure requiring hospitalization.
* Transmural myocardial infarction within the last 6 months.
* Acute bacterial or fungal infection requiring intravenous antibiotics at time of enrollment.
* Chronic Obstructive Pulmonary Disease exacerbation or other respiratory illness requiring hospitalization or precluding study therapy.
* Hepatic insufficiency resulting in clinical jaundice and/or coagulation defects.
* Acquired Immune Deficiency Syndrome (AIDS) based upon current CDC definition. The need to exclude patients with AIDS from this protocol is necessary because the treatments involved in this protocol may be significantly immunosuppressive.
* Major medical illnesses or psychiatric impairments that, in the investigator's opinion, will prevent administration or completion of protocol therapy.
4 Years
30 Years
ALL
No
Sponsors
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Children's National Research Institute
OTHER
University of Florida
OTHER
Responsible Party
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Principal Investigators
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Duane Mitchell, MD, PhD
Role: STUDY_CHAIR
University of Florida
John Ligon, MD
Role: PRINCIPAL_INVESTIGATOR
University of Florida
Locations
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University of Florida Health
Gainesville, Florida, United States
Countries
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Other Identifiers
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OCR45772
Identifier Type: OTHER
Identifier Source: secondary_id
IRB202400861-A
Identifier Type: -
Identifier Source: org_study_id