vaccine immunotherapy for recurrent medulloblastoma and primitive neuroectodermal tumor

Conditions: Medulloblastoma; Neuroectodermal Tumor

Summary: immunotherapy is a specific approach to treating cancer that has shown promise in adult patients for the treatment of melanoma, malignant brain tumors, and other cancers. the study investigators will use the experience they have gained from these studies to try to improve the outcome for children affected by a recurrent brain tumor. approximately 35 patients with first recurrence of medulloblastoma (remb)/supratentorial primitive neuroectodermal tumors (pnets) will be treated with tumor-specific immune cells and dendritic cell vaccines to see what impact they have on the 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. 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. in this study, the investigators will treat patients with first recurrence remb/pnets after completion of definitive radiation therapy with autologous tumor-specific t cell immunotherapy (ttrna-xalt) plus ttrna-loaded dendritic cell vaccine. following surgical resection, biopsy, or cytology examination with confirmatory pathologic diagnosis, patients will be enrolled into group a (high-dose chemotherapy or hdc) or group b (non-myeloablative or nma salvage chemotherapy) based on eligibility for hdc. patients with localized relapse and have not failed hdc+ peripheral blood stem cell transplant (pbsct) previously will be enrolled into group a. patients with disseminated disease, have previously failed hdc+pbsct, or are otherwise considered poor candidates for hdc based on overall health status, but otherwise meet eligibility criteria, will be enrolled into group b. all patients will receive dc + xalt therapy.

Eligibility criteria:
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 (\> 101.5f) 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.

Keywords: medulloblastoma primitive neuroectodermal tumor