Abstract IA07: Using matrix protein affinity to modulate the tumor microenvironment

J. Ishihara, Ako Ishihara, Koichi Saskai, S. S. Lee, Mariko Yasui, Hiroyuki Abe, L. Potin, Peyman Hosseinchi, Kazuto Fukunaga, Michal M. Raczy, L. Gray, John-Michael Williford, M. Fukayama, Tiffany M. Marchell, A. Mansurov, A. T. Alpar, S. Kron, M. Swartz, J. Hubbell
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Abstract

Cancer immunotherapy with immune checkpoint inhibitors (CPI) and interleukin (IL)-2 has demonstrated clinical efficacy but is frequently accompanied with severe adverse events caused by excessive and systemic immune system activation. Here, we addressed this need by targeting both the CPI antibodies anti-cytotoxic T-lymphocyte antigen 4 antibody (CTLA4) + anti-programmed death-ligand 1 antibody (PD-L1) and the cytokine IL-2 to tumors via conjugation (for the antibodies) or recombinant fusion (for the cytokine) to a collagen-binding domain (CBD) derived from the blood protein von Willebrand factor (VWF) A3 domain, harnessing the exposure of tumor stroma collagen to blood components due to the leakiness of the tumor vasculature. We show that intravenously (i.v.) administered CBD protein accumulated mainly in tumors, for example 57% of total injected dose depositing in an orthotopic breast tumor model. The CBD was observed to localize throughout the tumor stroma, not merely in the subendothelial space. CBD conjugation or fusion decreased the systemic toxicity of both CTLA4+PD-L1 combination therapy and IL-2, for example eliminating hepatotoxicity with the CPI molecules and ameliorating capillary leak syndrome and pulmonary edema with IL-2. Both CBD-CPI and CBD-IL-2 significantly suppressed tumor growth compared to their unmodified forms in multiple murine cancer models, and both CBD-CPI and CBD-IL-2 increased tumor-infiltrating CD8+ T cells; increases in the ratio of effector CD8+ T cells to T regulatory cells were observed. In an orthotopic breast tumor model, combination treatment with CPI and IL-2 eradicated tumors in 9/13 animals with the CBD-modified drugs, whereas it did so in only 1/13 animals with the unmodified drugs. Thus, the A3 domain of von Willebrand factor can be used to engineer immunotherapies with high translational promise as systemically-administered tumor targeting drugs with improved safety and efficacy compared to their native forms. The targeting approach exploits vascular permeability in the tumor to render the ubiquitous extracellular matrix protein accessible in the tumor, while sparing most other tissues. Citation Format: Jun Ishihara, Ako Ishihara, Koichi Saskai, Steve Seung-Young Lee, Mariko Yasui, Hiroyuki Abe, Lambert Potin, Peyman Hosseinchi, Kazuto Fukunaga, Michal M. Raczy, Laura T. Gray, John-Michael Williford, Masashi Fukayama, Tiffany M. Marchell, Aslan Mansurov, Aaron T. Alpar, Stephen J. Kron, Melody Swartz, Jeffrey A. Hubbell. Using matrix protein affinity to modulate the tumor microenvironment [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA07.
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摘要:利用基质蛋白亲和力调节肿瘤微环境
使用免疫检查点抑制剂(CPI)和白细胞介素(IL)-2进行癌症免疫治疗已经证明了临床疗效,但经常伴随着过度和全身免疫系统激活引起的严重不良事件。在这里,我们通过将CPI抗体(抗细胞毒性t淋巴细胞抗原4抗体(CTLA4) +抗程序性死亡配体1抗体(PD-L1)和细胞因子IL-2结合(针对抗体)或重组融合(针对细胞因子)到来自血液蛋白血管性血液病因子(VWF) A3结构域的胶原结合结构域(CBD)靶向肿瘤来解决这一需求。利用肿瘤间质胶原暴露于由于肿瘤血管渗漏的血液成分。我们发现静脉(i.v.)给药的CBD蛋白主要在肿瘤中积累,例如,57%的总注射剂量沉积在原位乳腺肿瘤模型中。观察到CBD在整个肿瘤基质中都有分布,而不仅仅是在内皮下空间。CBD结合或融合降低了CTLA4+PD-L1联合治疗和IL-2的全身毒性,例如CPI分子消除肝毒性,IL-2改善毛细血管渗漏综合征和肺水肿。在多种小鼠癌症模型中,与未修饰的形式相比,CBD-CPI和CBD-IL-2均显著抑制肿瘤生长,并且CBD-CPI和CBD-IL-2均增加肿瘤浸润性CD8+ T细胞;观察到效应CD8+ T细胞与T调节性细胞的比例增加。在原位乳腺肿瘤模型中,CPI和IL-2联合治疗在9/13只使用cbd修饰药物的动物中根除了肿瘤,而使用未修饰药物的动物中只有1/13的动物根除了肿瘤。因此,血管性血液病因子的A3结构域可用于设计具有高翻译前景的免疫疗法,作为系统给药的肿瘤靶向药物,与天然形式相比,具有更高的安全性和有效性。靶向方法利用肿瘤中的血管通透性,使无处不在的细胞外基质蛋白在肿瘤中可接近,同时保留大多数其他组织。引文形式:石原慎子、石原慎子、笹井浩一、Steve seseyoung Lee、Mariko Yasui、Hiroyuki Abe、Lambert Potin、Peyman Hosseinchi、Kazuto Fukunaga、michael M. Raczy、Laura T. Gray、John-Michael Williford、Masashi fuyamama、Tiffany M. Marchell、Aslan Mansurov、Aaron T. Alpar、Stephen J. Kron、Melody Swartz、Jeffrey A. Hubbell。利用基质蛋白亲和力调节肿瘤微环境[摘要]。第四届CRI-CIMT-EATI-AACR国际癌症免疫治疗会议:将科学转化为生存;2018年9月30日至10月3日;纽约,纽约。费城(PA): AACR;癌症免疫学杂志,2019;7(2增刊):摘要1 - 7。
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