Engineering the brain tumor microenvironment enhances the efficacy of dendritic cell vaccination: implications for clinical trial design.
Engineering the brain tumor microenvironment enhances the efficacy of dendritic cell vaccination: implications for clinical trial design.
复制标题
DOI：
10.1158/1078-0432.ccr-11-0915
复制
发表时间：
2011-07-15
期刊：
影响因子：
--
通讯作者：
Castro MG
中科院分区：
文献类型：
--
作者：
Mineharu Y;King GD;Muhammad AK;Bannykh S;Kroeger KM;Liu C;Lowenstein PR;Castro MG
多形性胶质母细胞瘤（GBM）是一种致命的原发性脑肿瘤。使用树突状细胞（DC）疫苗接种的GBM的临床试验导致抗肿瘤免疫应答。在本文中，我们测试了这样的假设，即将原位（瘤内）Ad-Flt 3L/Ad-TK介导的基因治疗与DC疫苗接种相结合将增加治疗功效和抗肿瘤免疫。我们首先评估了在同源脑肿瘤模型中由Ad-TK（+GCV）、替莫唑胺（TMZ）或冻融循环（FTC）产生的肿瘤裂解物的免疫原性。我们还评估了表型标志物、细胞因子释放和由fms样酪氨酸激酶3配体（Flt 3L）+ IL-6或粒细胞-巨噬细胞集落刺激因子（GM-CSF）和IL-4产生的骨髓源性DC的吞噬作用。在用以下疫苗接种后评估肿瘤进展的抑制和抗GBM抗体的产生：（i）肿瘤细胞裂解物，（ii）用加载有Ad-TK/GCV、TMZ或FTC产生的肿瘤裂解物的Flt 3L/IL 6或GM-CSF/IL 4产生的DC，或（iii）与原位Ad-Flt 3L/Ad-TK基因疗法组合的DC。用Ad-TK/GCV或TMZ产生的负载肿瘤细胞裂解物的DC导致吞噬作用、治疗功效和体液免疫应答水平的增加。原位免疫基因治疗联合DC疫苗接种导致约90%的动物脑肿瘤消退和长期存活，与单独治疗相比显着增加。我们的研究结果表明，使用肿瘤内Ad-Flt 3L/Ad-TK介导的基因治疗来修饰肿瘤微环境增强DC疫苗接种诱导的治疗效果和抗肿瘤免疫。这些数据支持新的I期临床试验，以评估这种联合方法的安全性和有效性。
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.