Phase I immunotherapy trial using glioblastoma apoptotic body-pulsed dendritic cells.
ABSTRACT
Background: We recently reported that tumor cell vaccines cultured in 5% oxygen (O2) had enhanced the immunogenicity relative to those grown in standard atmospheric O2. In order to develop an “off-the-shelf” source of whole cell antigen we screened a panel of primary glioblastoma (GBM) cell lines, leading to identification of (GBM6) as an ideal candidate. GBM6 was extensively characterized and shown to express glioma-associated antigens (IL13Ra2, Sox2, Epha2, etc.). A Phase I clinical trial was initiated to evaluate the safety and feasibility of a vaccine consisting of dendritic cells (DC) pulsed with apoptotic bodies from GBM6 grown in 5% O2.
Methods: Patients ranging from 3 to 71 years with recurrent GBM (n=6) or ependymoma (n=1) were enrolled. Monocytes were collected via apheresis, matured into DC and pulsed with apoptotic bodies derived from GBM6. The first three patients received escalating doses of DC (5×106, 10×106, and 15×106), the remainder received 15 x 106 DC. Pulsed dendritic cellswere injectedsubcutaneously into the supra-scapular region. Imiquimod cream was applied at the injection site just prior to vaccination and 24 hours later. The vaccine schedule dictated administration every 2 weeks for 8 weeks (total of 5 doses) then monthly to progression or a total of 52 weeks. Prior to each vaccination, patients met eligibility parameters and had no progression on MRI. Patients were imaged monthly and blood was drawn to evaluate toxicity and immune response.
Results: No vaccine-related toxicity has been reported. Time to progression ranges from 6.5 weeks for the patient treated at the first dose level to 35 weeks for one patient receiving 15 x 106 DC. The latter patient experienced a partial response at 20 weeks. Two patients have stable disease at 18.5 and 28 weeks, respectively. One patient was not evaluable. Flow cytometric analysis demonstrated expansion of central memory T cells amidst declining effector memory cells following vaccination in three patients at a dose of 15×106 DC.
Conclusions: Apoptotic body-pulsed DC vaccination was well tolerated and preliminarily demonstrated clinical activity but a minimum of 15×106 DC was required for a modulation of central memory T cells.