Treatment of Canine Oral Melanoma with Nanotechnology-Based Immunotherapy and Radiation
Treatment of Canine Oral Melanoma with Nanotechnology-Based Immunotherapy and Radiation
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DOI：
10.1021/acs.molpharmaceut.8b00126
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发表时间：
2018-09-01
影响因子：
4.9
通讯作者：
Fiering, Steven N.
中科院分区：
文献类型：
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作者：
Hoopes, P. Jack;Wagner, Robert J.;Fiering, Steven N.
随着癌症免疫治疗的整体兴趣的扩大，放射治疗相关免疫反应的存在和益处引起了极大的兴趣。放射肿瘤的病理评估很少显示一致的免疫或炎症反应。最新的信息表明，基于辐射的全身免疫反应可能比先前认为的更常见，具有更大的治疗潜力，主要与“离焦效应”有关。然而，为了具有一致的价值，放射治疗(RT)的免疫刺激潜力显然需要与其他免疫治疗努力相结合来支持。在这项研究中，使用自发性犬口腔黑色素瘤模型，我们评估了两种基于纳米技术的免疫佐剂联合RT的疗效和肿瘤免疫病理学。免疫佐剂是在肿瘤内注射的，方法是将免疫刺激试剂放入已识别的肿瘤中，并将肿瘤中的内源性抗原用作构成疫苗的抗原/佐剂组合中的抗原。放射治疗包括在12天内给予局部6×6Gy肿瘤方案。免疫佐剂是以植物为基础的病毒样纳米颗粒(VLP)和直径110 nm的磁性氧化铁纳米颗粒(MNPH)，该纳米颗粒被交变磁场(AMF)激活以产生中等温度(43℃/60min)。RT单独使用或与一种或两种佐剂联合使用。放疗期间瘤内分别给予VLP(4×200 mg/g)和mNPH(2×7.5 mg/g肿瘤)。所有患者在开始治疗前都接受了诊断性活检和基于CT的三维放射治疗计划。患者在治疗后14-21天进行临床评估，治疗后3个月每月评估一次，此后每两个月评估一次。治疗前和治疗后14~21天分别进行肿瘤免疫组织病理学检查。结果表明，在低分割放疗方案中加入VLP和/或mNPH可增加免疫细胞在肿瘤中的渗透，延长肿瘤控制间隔，具有重要的全身治疗潜力。
The presence and benefit of a radiation therapy-associated immune reaction is of great interest as the overall interest in cancer immunotherapy expands. The pathological assessment of irradiated tumors rarely demonstrates consistent immune or inflammatory response. More recent information, primarily associated with the "abscopal effect", suggests a subtle radiation-based systemic immune response may be more common and have more therapeutic potential than previously believed. However, to be of consistent value, the immune stimulatory potential of radiation therapy (RT) will clearly need to be supported by combination with other immunotherapy efforts. In this study, using a spontaneous canine oral melanoma model, we have assessed the efficacy and tumor immunopathology of two nanotechnology-based immune adjuvants combined with RT. The immune adjuvants were administered intratumorally, in an approach termed "in situ vaccination", that puts immunostimulatory reagents into a recognized tumor and utilizes the endogenous antigens in the tumor as the antigens in the antigen/adjuvant combination that constitutes a vaccine. The radiation treatment consisted of a local 6 x 6 Gy tumor regimen given over a 12 day period. The immune adjuvants were a plant-based virus-like nanoparticle (VLP) and a 110 nm diameter magnetic iron oxide nanoparticle (mNPH) that was activated with an alternating magnetic field (AMF) to produce moderate heat (43 degrees C/60 min). The RT was used alone or combined with one or both adjuvants. The VLP (4 X 200 mu g) and mNPH (2 X 7.5 mg/gram tumor) were delivered intratumorally respectively during the RT regimen. All patients received a diagnostic biopsy and CT-based 3-D radiation treatment plan prior to initiating therapy. Patients were assessed clinically 14-21 days post-treatment, monthly for 3 months following treatment, and bimonthly, thereafter. Immunohistopathologic assessment of the tumors was performed before and 14-21 days following treatment. Results suggest that addition of VLPs and/or mNPH to a hypofractionated radiation regimen increases the immune cell infiltration in the tumor, extends the tumor control interval, and has important systemic therapeutic potential.