Engineering the brain tumor microenvironment enhances the efficacy of dendritic cells` vaccination: implications for clinical trials design.
Posted on: 06/16/2011
Clin Cancer Res. 2011 Jun 1. [Epub ahead of print]
Engineering the brain tumor microenvironment enhances the efficacy of dendritic cells' vaccination: implications for clinical trials design.
Mineharu Y, King GD, Muhammad AG, Bannykh S, Kroeger KM, Liu C, Lowenstein PR, Castro MG.
GENE THERAPY RESEARCH INSTITUTE, Cedars-Sinai Medical Center.
Glioblastoma multiforme (GBM) is a deadly primary brain tumor. Clinical trials for GBM using dendritic cell (DC) vaccination resulted in anti-tumor immune responses. Herein we tested the hypothesis that combining in situ (intratumoral) Ad-Flt3L/Ad-TK-mediated gene therapy with DC vaccination would increase therapeutic efficacy and anti-tumor immunity.
We first assessed the immunogenicity of tumor lysates generated by Ad-TK (+GCV), temozolomide (TMZ) or freeze/thawing cycles (FTC) in a syngeneic brain tumor model. We also assessed phenotypic markers, cytokine release, and phagocytosis of bone marrow derived DCs generated by fms-like tyrosine kinase 3 ligand (Flt3L) + IL-6 or by granulocyte-macrophage colony-stimulating factor (GM-CSF) and IL-4. Inhibition of tumor progression and production of anti-GBM antibodies was assessed following vaccination with (i) tumor cell lysates, (ii) DCs generated with either Flt3L/IL6 or GM-CSF/IL4 loaded with either Ad-TK/GCV, TMZ, or FTC generated tumor lysates, or (iii) DCs in combination with in situ Ad-Flt3L/Ad-TK gene therapy.
DCs loaded with tumor cell lysates generated with either Ad-TK/GCV or TMZ led to increased levels of phagocytosis, therapeutic efficacy and humoral immune response. In situ immunogene therapy in combination with DC vaccination led to brain tumor regression and long-term survival in ~90% of animals, a significant increase when compared to either therapy alone.
Our results indicate that modifying the tumor microenvironment using intra-tumoral Ad-Flt3L/Ad-TK-mediated gene therapy potentiates therapeutic efficacy and anti-tumor immunity induced by DC vaccination. These data support novel Phase I clinical trials to assess the safety and efficacy of this combined approach.
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