Vaccine Immunotherapy for Recurrent Medulloblastoma and Primitive Neuroectodermal Tumor

Malignant brain tumors now represent the most frequent cause of cancer death in children.
Despite aggressive and highly toxic multi-modality therapy including surgery, craniospinal
radiation, and high-dose chemotherapy coupled with peripheral blood stem cell
transplantation, almost half the children diagnosed with the most common malignant brain
tumors, medulloblastoma (MB) and primitive neuroectodermal tumors (PNET), will still die from
recurrent disease. Furthermore, survivors are often left with severe and lifelong
treatment-associated cognitive and motor deficits. The development of more effective and
tumor-specific therapies that will not add further toxicity to existing treatments is
paramount in improving clinical outcomes for children affected by MB/PNETs. Immunotherapy
targeting tumor-specific antigens expressed within brain tumors is a modality potentially
capable of meeting this clear and urgent need.

Despite considerable advancements and promising clinical results observed in immunotherapy
trials directed against adult malignant brain tumors, efforts in the immunologic treatment of
pediatric brain tumors have been limited to relatively few notable studies. This is due, at
least in part, to the often limited viable tumor tissue available for tumor cell-based
vaccine preparations, and the lack of identification of consistently expressed tumor-specific
antigens within these cancers.

The use of total tumor RNA (TTRNA)-loaded dendritic cells (DCs) was pioneered at Duke
University, as a novel platform for inducing potent immunologic responses against the variety
of uncharacterized and patient-specific antigens present within malignant tumor cells. Duke
demonstrated that sufficient RNA for clinical vaccine preparations can be amplified with high
fidelity using existing molecular technologies from as few as 500 isolated pediatric and
adult brain tumor cells, thus allowing vaccine preparation from surgical biopsies and even
microdissected archival tumor specimens. In this study, the investigators will treat
recurrent MB/PNETs during hematopoietic recovery from chemotherapy.

Immunotherapy administered during recovery from chemotherapy may have tremendous advantages,
as adoptive cellular therapy following lymphodepletive conditioning regimens has emerged as
the most effective treatment strategy for advanced and refractory melanoma. Our hypothesis is
that DC + ex vivo expanded Autologous Lymphocyte Transfer (xALT) therapy targeting recurrent
MB/PNETs during recovery from myeloablative chemotherapy will be safe and will prolong
survival in children and young adults with recurrent MB/PNETs.

Inclusion Criteria:

Screening:

- Age ≤ 30 years of age.

- Suspected first recurrence/progression of MB/PNET since completion of definitive focal
+/- craniospinal irradiation. Disease progression prior to receiving definitive focal
+/- craniospinal irradiation will not disqualify patients from enrollment if they have
subsequently failed definitive radiotherapy and are at first recurrence/progression at
time of enrollment. Patients who are unable to receive radiation therapy due to
genetic disorders that put them at significant risk for radiation-induced secondary
malignancies (i.e. Gorlin's syndrome or NF1 mutation) are eligible for enrollment at
first disease recurrence/progression.

Re-MATCH Protocol:

- Patients must have histologically confirmed recurrent MB/PNET that is a first
relapse/progression after completion of definitive radiotherapy +/- craniospinal
irradiation. Patients with a first relapse/progression who are unable to receive
radiation therapy due to genetic disorders that put them at significant risk for
radiation-induced secondary malignancies (ie. Gorlin's syndrome or NF1 mutation) are
eligible for enrollment.

- Patients with neurological deficits should have deficits that are stable for a minimum
of 1 week prior to registration.

- Karnofsky Performance Status of ≥ 50% or Lansky Performance Score of ≥ 50.

- Absolute Neutrophil Count (ANC) ≥ 1000/µl (unsupported).

- Platelets ≥ 100,000/µl (unsupported).

- Hemoglobin > 8 g/dL (may be supported).

- Serum creatinine ≤ upper limit of institutional normal

- Bilirubin ≤ 1.5 times upper limit of normal for age.

- Serum Glutamic Oxaloacetic Transaminase (ALT) ≤ 3 times institutional upper limit of
normal for age.

- Serum Glutamic Oxaloacetic Transaminase (AST) ≤ 3 times institutional upper limit of
normal for age.

- Patients of childbearing or child-fathering potential must be willing to use a
medically acceptable form of birth control, which includes abstinence, while being
treated on this study.

- Patient or patient guardian consent to peripheral blood stem cell (PBSC) and/or bone
marrow harvest following registration if PBSC or bone marrow (CD34 count of at least
2x10^6/kg) has not been previously stored and available for use.

- Signed informed consent according to institutional guidelines must be obtained prior
to registration.

Exclusion Criteria:

- Pregnant or need to breast feed during the study period.

- Active infection requiring treatment or an unexplained febrile (> 101.5o F) illness.

- Known immunosuppressive disease, human immunodeficiency virus infection, or carriers
of Hepatitis B or Hepatitis C virus.

- Patients with active renal, cardiac (congestive cardiac failure, myocardial
infarction, myocarditis), or pulmonary disease.

- Patients receiving concomitant immunosuppressive agents for medical condition.

- Patients who need definitive radiotherapy for treatment of recurrent MB/PNET. Focal
boost radiotherapy may be delivered prior to immunotherapy if required for local
control.

- Patients receiving any other concurrent anticancer or investigational drug therapy.

- Patients with any clinically significant unrelated systemic illness (serious
infections or significant cardiac, pulmonary, hepatic or other organ dysfunction).

- Patients with inability to return for follow-up visits or obtain follow-up studies
required to assess toxicity to therapy.