Phase I/II: Decitabine/Vaccine Therapy in Relapsed/Refractory Pediatric High Grade Gliomas/Medulloblastomas/CNS PNETs

One of the challenges of the practical application of immunotherapy for brain tumors is the
lack of expression of tumor antigens as well as the down-regulation of Major
Histocompatibility Complex (MHC Class I and II ) molecules, which are needed for antigen
presentation. Considering the ability of 5-aza-2-deoxycytidine (DAC) to facilitate the
expression of cancer/testis (CT) antigens and major histocompatibility complex molecules
(MHC) and the fact that it has good blood brain barrier penetration, it is reasonable to test
this approach in a vaccine study for patients who have experienced disease recurrence. The
use of a combined approach to tumor immunotherapy - antigen upregulation followed by
vaccination - has not been studied in this patient population, and there is a strong biologic
rationale for this strategy.

Patients with pediatric brain tumors (medulloblastoma, CNS PNET, high grade glioma) who have
experienced disease relapse or progressive refractory disease will be eligible. Each cycle
will consist of DAC at low dose administered over a 5 day period, followed by two weekly
vaccinations consisting of autologous dendritic cells pulsed with pooled, overlapping peptide
mixes derived from full-length MAGE-A1, MAGE-A3, and NY-ESO-1. This dose of DAC is lower than
all previously reported doses that have been safely administered in adult patients with
Myelodysplastic syndromes (MDS) and Acute myeloid leukemia (AML), and was used in a previous
protocol for relapsed and refractory pediatric neuroblastoma and sarcomas. A novel way of
stimulating CD4 and CD8 antigen specific T cells is to use a dendritic cells (DC) vaccine
approach in which the cells are pulsed with overlapping peptides derived from these antigens,
so that patients from several different HLA backgrounds can be enrolled. Overlapping peptide
mixes derived from full-length NY-ESO-1, MAGE-A1, or MAGE-A3 have been acquired and consists
of 15-mers, with 11 amino acid overlap. The number of DC given in our study (8-10 x 106
peptide pulsed DC) is within the range of doses given in previous studies. Vaccinations are
spaced at weekly intervals, based on multiple previous studies in which this approach is
taken, and the fact that in vitro re-stimulation of cytolytic T lymphocyte (CTL) generally
occurs on a weekly basis. Granulocyte-macrophage colony-stimulating factor (GM-CSF) is given
days 1 through 5 during vaccine weeks, to minimize leukopenia from DAC and to help facilitate
antigen presenting cell function. The adjuvant poly-interstitial Cajal-like cell (ICLC;
Hiltonol) will be injected immediately after and adjacent to DC vaccine site to enhance DC
maturation. We will accrue 10 patients with relapsed, refractory, or progressive pediatric
brain tumors over a 3 year period. Cycles will repeat every five weeks, for two cycles.
Patients who do not have disease progression after two cycles may receive an additional two
cycles of therapy.

Inclusion Criteria:

Criteria for enrollment:

- Relapsed medulloblastoma, CNS PNET, or high grade glioma. Confirmatory biopsy is
required at time of initial diagnosis.

- Because of rapid clinical progression and decline at time of relapse in patients with
grade IV gliomas and diffuse intrinsic pontine gliomas (DIPGs), and the 4-6 weeks
required to develop vaccine, patients with these tumors will be eligible to enroll and
have DCs harvested and stored at the time of diagnosis, but will not be treated with
vaccine until time of relapse.

- Age: Patients must be 2 to 25 years of age.

Criteria for treatment:

- The patient must have experienced relapsed, progressive, or refractory disease.

- The patient may have gross tumor that has been treated with chemotherapy or radiation
prior to study treatment.

- The patient must have received standard therapy for their tumor.

- The patient must be at least 90 days from primary radiotherapy.

- Hematologic Function: absolute neutrophil (ANC): 1000/uL; Platelet count: 75,000/uL.

- Renal Function: Creatinine clearance or radioisotope glomerular filtration rate (GFR)
70ml/min/1.73 m2 .

- Cardiac Function: Patient must have normal cardiac function documented by:

- Ejection fraction (>55%) documented by echocardiogram or radionuclide multigated
acquisition (MUGA) scan evaluation OR

- Fractional shortening (≥28%) documented by echocardiogram

- Liver Function: Total bilirubin 1.5x normal for age, and serum glutamate pyruvate
transaminase (SGPT (ALT)) and serum glutamate oxaloacetate transaminase (SGOT (AST))
3x normal for age.

- Room air pulse oximetry >94%.

- Male and female sexually active patients of reproductive age who wish to participate
must agree to use acceptable contraception.

- Lansky/Karnofsky performance scale > 50, electrocorticogram (ECOG) < or = 2 (Appendix
I).

Exclusion Criteria:

- Patient is pregnant.

- Patients with a positive result for any of the following diagnostic tests: Hep B Ag,
Hep B Core Ab, Hep C Ab, HIV-1 Ab, HIV-2 Ab, human T-cell leukemia virus (HTLV-1 Ab),
HTLV-2 Ab, rapid plasma reagin (RPR).

- Patient has a history of autoimmune disease, specifically inflammatory bowel disease,
systemic lupus erythematosis, or rheumatoid arthritis.

- Patient is receiving high doses of systemic corticosteroids or concurrent chemotherapy
at the time of beginning study treatment. (Maximum dose of dexamethasone allowed is
0.1mg/kg/day not to exceed 4mg/day.)

- Patient has a known systemic hypersensitivity to DAC, Hiltonol, or any vaccine
component.