This is a phase l/ll single-institutional trial designed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT), and to evaluate the induction of an immune and clinical response (secondary objectives) of glioma associated antigen (GAA) -peptide loaded """"""""type-1-polarized dendritic cells"""""""" (ccDC1) vaccines in patients with recurrent malignant gliomas. Active vaccination strategies may develop as an effective and safe modality for this disease entity, which still remains dismal. Although several groups, including ours, have demonstrated the safety and preliminary efficacy of whole glioma cell-based vaccine approaches, GAA-specific vaccines are expected to be safer and more feasible than the whole cell approaches. We have previously described identification of an HLA-A2-restricted CD8+ T cell epitope derived from the GAA interleukin-13 receptor cc2-chain (IL-13Rct2). In addition, we have found other GAA- derived CTL epitopes, such as EphA2 (883-891) and YKL-40 (202-211), as well as modified peptides that can induce higher levels of CTL reactivity against IL-13Ra2 (345-353). To our knowledge, this is one of the first glioma-vaccine trials that target multiple antigens. In addition, we plan to utilize a novel culture method for producing DCs that preferentially induce Type-1 CTL responses (i.e., cxDC1). Patients with recurrent anaplastic astrocytoma or glioblastoma multiforme will receive at least 4 cycles of aDC1s loaded with GAA- epitopes by ultrasound-guided injection into lymph nodes with a dose escalation for DC-numbers to determine the MTD and to evaluate the effect of DC-doses to immune reactivity. We will examine the following specific hypotheses: 1. This form of vaccination will be safe; endpoints will therefore include determination of the MTD and DLT of this regimen; and 2. This form of vaccination will induce measurable T cell responses against the targeted GAAs. We will assess the immunological response against GAA- epitopes in patients receiving this form of vaccine primarily using interferon-y enzyme-linked immuno-spot (ELISPOT) assays. In addition, we will assess the preliminary anti-tumor clinical activity of the vaccines as measured by radiological response (MRI), 4 and 6 month-progression-free survival and overall survival. Information from this pilot study will establish a basis to design subsequent trials with patient populations in which more significant clinical benefit might be realized. ? ? ?
| Okada, Hideho; Weller, Michael; Huang, Raymond et al. (2015) Immunotherapy response assessment in neuro-oncology: a report of the RANO working group. Lancet Oncol 16:e534-e542 |
| Pollack, Ian F; Jakacki, Regina I; Butterfield, Lisa H et al. (2013) Ependymomas: development of immunotherapeutic strategies. Expert Rev Neurother 13:1089-98 |
| Okada, Hideho; Kalinski, Pawel; Ueda, Ryo et al. (2011) Induction of CD8+ T-cell responses against novel glioma-associated antigen peptides and clinical activity by vaccinations with {alpha}-type 1 polarized dendritic cells and polyinosinic-polycytidylic acid stabilized by lysine and carboxymethylcellulose in J Clin Oncol 29:330-6 |
