Purpose

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.

Condition

Eligibility

Eligible Ages
Between 3 Years and 21 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

Criteria


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

- Residual post-surgical disease burden < 3 cm as defined by longest perpendicular
diameter of contrast enhancing tumor on post-operative MRI 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 registration.

Prior to 1st Vaccine

- Off corticosteroids or weaning to a minimal/stable dose of replacement steroids ≤ 4
mg/day within 1 week of scheduled DC vaccination.

Exclusion Criteria:

- HGG biopsy only subjects are not eligible for this study

- Midline unresectable tumors

- Gliomatosis Cerebri

- Residual post-surgical disease burden > 3 cm as defined by longest perpendicular
diameter of contrast enhancing tumor on MRI.

- 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.

- Subjects who require corticosteroids above physiologic doses (>4mg/day or equivalent
dexamethasone).

- 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.

Study Design

Phase
Phase 1
Study Type
Interventional
Allocation
Non-Randomized
Intervention Model
Sequential Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Group A
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
    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.
  • Drug: Dose-intensified TMZ
    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.
  • Biological: TTRNA-xALT
    During TMZ Cycle 6 and with DC vaccine #8, an infusion of T-cells will be administered to all subjects.
  • 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.
Experimental
Group B
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
    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.
  • Drug: Dose-intensified TMZ
    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.
  • Biological: Autologous Hematopoietic Stem cells (HSCs)
    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.
  • Biological: TTRNA-xALT
    During TMZ Cycle 6 and with DC vaccine #8, an infusion of T-cells will be administered to all subjects.
  • 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.

Recruiting Locations

Children's National and nearby locations

Children's National Hospital
Washington, District of Columbia 20010
Contact:
Brittany Hodik
202-476-6493
bhodik@childrensnational.org

More Details

NCT ID
NCT03334305
Status
Recruiting
Sponsor
University of Florida

Study Contact

Marcia Hodik, RN
352-273-6971
marcia.hodik@neurosurgery.ufl.edu

Detailed Description

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.