This phase I/II trials evaluates the feasibility, safety and efficacy of an individualized cancer vaccine, based on autologous, tumor-lysate loaded dendritic cells in children and adolescents with relapsed high-grade gliomas. In addition, regulatory T cells are depleted by a short cycle of metronomic cyclophosphamide upfront of the vaccine in order to facilitate induction of immune responses. Therapeutic DC vaccines are followed by four cycles of Nivo/Ipi double checkpoint blockade and a Nivolumab monotherapy maintenance in order to optimize the induced T-cell response.
Relapsed high-grade gliomas (in the following addressed as high-grade gliomas = HGG) in children and adolescents represent a very bad prognosis group for which a recommended standard salvage therapy is currently not available. Combination of Dendritic Cell (DC) vaccination, metronomic cyclophosphamide, and checkpoint blockade will be investigated in the present trial as a new treatment strategy for these patients: metronomic cyclophosphamide has been shown to significantly reduce numbers of regulatory T cells (Treg) without inducing general leukopenia. DCs might induce tumour-directed immune responses thereby facilitating long-term remissions. Efficacy of primed T-cell responses by the vaccine will potentially be enhanced by the application of checkpoint inhibitors Nivolumab (antiPD-L1) and Ipilimumab (antiCTLA4) in the post-vaccine phase and during maintenance. Cyclophosphamide is an established drug used as an anti-cancer or immunosuppressive substance since decades, with extensive experience when used in low, non-myeloablative dosages. DCs represent an innovative new strategy in cellular immunotherapy. DCs in cancer patients have been used in a number of smaller studies, and in some of these trials, promising results could be obtained. Several studies showed a trend towards a prolonged overall survival with a few long-term survivors which is otherwise extremely rare in this high-risk population. Results seemed to be more favourable in pediatric than in adult patients. Checkpoint inhibitors (antiPD-L1 and/or antiCTLA4) have been shown to exhibit synergistic effects with vaccines in preclinical models, and prelimnary data of several early stage trials have shown promising results. Therefore, our study aims to improve the efficacy of a DC-based therapeutic vaccine by optimizing the conditions upfront of the vaccine (Treg depletion) and improving T-cell responses by checkpoint blockade after the vaccine in the effector phase. In conclusion, this study will exploit the optimal efficacy of a therapeutic vaccine in children and adolescents with relapsed HGG.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
24
oral metronomic cyclophosphamide
resection of relapsed tumor in order to improve clinical condition of the patient and to acquire tumor tissue for vaccine generation
4 weekly intradermal injections of lysate-loaded dendritic cells, followed by 3 monthly boost vaccines with tumor lysate and further boost vaccines every three months
Immediately one week after the DC-induction vaccines, patients will receive four applications of Nivolumab/Ipilimumab double checkpoint blockade in threeweekly intervals, followed by Nivolumab monotherapy every month for a total duration of one year.
University Children's Hospital
Würzburg, Bavaria, Germany
6 month overall survival
overall survival 6 months after diagnosis of relapse
Time frame: 6 months
overall survival
overall survival
Time frame: 12-24 months
progression-free survival
progression-free survival
Time frame: 12-24 months
toxicity metronomic cyclophosphamide
frequency of adverse events associated with metronomic cyclophosphamide
Time frame: 12-24 months
toxicitiy vaccine
frequency of adverse events associated with the vaccine
Time frame: 12-24 months
toxicity checkpoint blockade
frequency of AEs/SAEs associated with Nivolumab and/or Ipilimumab
Time frame: 12-24 months
Treg frequency
frequency of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide in % of CD3+
Time frame: 12-24 months
Treg numbers
absolute numbers of CD4+CD25+CD127- regulatory T cells under metronomic cyclophosphamide per µl blood
Time frame: 12-24 months
T-cell response
Interferon-gamma Cytotoxic T cell (CTL) assay
Time frame: 12-24 months
serum cytokine levels
Tru Culture cytokine array
Time frame: 12-24 months
correlation with histopathological tumor characteristics
correlation of outcome/immune response with histopathology etc.
Time frame: 12-24 months
This platform is for informational purposes only and does not constitute medical advice. Always consult a qualified healthcare professional.