Department of Immunohematology and Blood Transfusion, Leiden University Medical Center; ISA Pharmaceuticals, Leiden, the Netherlands.
Clin Cancer Res. 2011 Apr 15;17(8):2270-80. doi: 10.1158/1078-0432.CCR-10-2888. Epub 2011 Mar 9.
Immunotherapy against tumors with anti-CD40 agonistic antibodies has been extensively studied in preclinical animal models and recently also in clinical trials. Although promising results have been obtained, antibody (Ab)-related toxicity has been a limiting factor. We reasoned that strict local activation of tumor-specific CD8 T cells through stimulation of CD40 on the dendritic cells (DC) in the tumor area while excluding systemic stimulation might be sufficient for effective tumor eradication and can limit systemic toxicity.
Preclinical in vivo models for immunogenic tumors were used to investigate the potential of delivering a nontoxic dose of agonistic anti-CD40 Ab to the tumor region, including draining lymph node, in a slow-release formulation (montanide).
The delivery of anti-CD40 monoclonal Ab, formulated in slow-release Montanide ISA-51, reprograms CTLs by inducing local but not systemic DC activation, resulting in effective tumor-specific CTL responses that eradicate local and distant tumors. Adverse side effects, assayed by organ histology and liver enzymes in the blood, were much lower after local anti-CD40 Ab delivery than systemic administration. The local delivery of anti-CD40 Ab activates only CTLs against antigens presented in the tumor-draining area, because unrelated distant tumors expressing different tumor antigens were not eradicated.
These results establish a novel therapeutic principle that local delivery and slow release of agonistic anti-CD40 Ab to the tumor-draining area effectively activates local tumor-specific CD8 T cells to become systemic effectors without causing systemic toxicity or nonspecific CTL activation. These findings have important implications for the use of anti-CD40 therapies in patients.
用抗 CD40 激动性抗体进行抗肿瘤免疫治疗已在临床前动物模型中得到广泛研究，最近也在临床试验中进行了研究。尽管取得了有希望的结果，但抗体（Ab）相关毒性一直是一个限制因素。我们推断，通过刺激肿瘤区域中的树突状细胞（DC）上的 CD40 来严格局部激活肿瘤特异性 CD8 T 细胞，同时排除全身刺激，可能足以有效清除肿瘤并限制全身毒性。
使用免疫原性肿瘤的临床前体内模型来研究将非毒性剂量的激动性抗 CD40 Ab 递送至肿瘤区域（包括引流淋巴结）的潜力，包括在缓释制剂（montanide）中。
递送抗 CD40 单克隆 Ab，用缓释 Montanide ISA-51 配制，通过诱导局部而非全身 DC 激活来重新编程 CTL，导致有效的肿瘤特异性 CTL 反应，从而根除局部和远处肿瘤。通过器官组织学和血液中的肝酶检测，与全身给药相比，局部给予抗 CD40 Ab 后不良反应要低得多。局部给予抗 CD40 Ab 仅激活针对引流区域肿瘤中呈现的抗原的 CTL，因为表达不同肿瘤抗原的无关远处肿瘤未被根除。
这些结果确立了一种新的治疗原则，即向肿瘤引流区域局部给予和缓慢释放激动性抗 CD40 Ab 可有效激活局部肿瘤特异性 CD8 T 细胞，成为全身效应物，而不会引起全身毒性或非特异性 CTL 激活。这些发现对 CD40 抗体治疗在患者中的应用具有重要意义。
