Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.
Safety and feasibility of an in situ vaccination and immunomodulatory targeted radionuclide combination immuno-radiotherapy approach in a comparative (companion dog) setting.
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DOI：
10.1371/journal.pone.0255798
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发表时间：
2021
期刊：
影响因子：
3.7
通讯作者：
Vail DM
中科院分区：
文献类型：
--
作者：
Magee K;Marsh IR;Turek MM;Grudzinski J;Aluicio-Sarduy E;Engle JW;Kurzman ID;Zuleger CL;Oseid EA;Jaskowiak C;Albertini MR;Esbona K;Bednarz B;Sondel PM;Weichert JP;Morris ZS;Hernandez R;Vail DM
小鼠同系肿瘤模型已经揭示了原发性肿瘤原位疫苗接种联合靶向放射性核素治疗对继发性或转移性肿瘤的有效全身抗肿瘤应答。在这里，我们提出的安全性和可行性的研究，这种方法在相关的翻译伴侣狗模型（n = 17只狗）与晚期癌症。在患有晚期癌症的伴侣犬中单独或联合使用联合免疫-放射治疗方法的三个组成部分。原位疫苗接种是通过给予低分割外照射放疗和瘤内注射hu14.18-IL 2融合免疫细胞因子到指数肿瘤来实现的。随后将原位疫苗接种与靶向放射性核素治疗相结合，使用IV 86 Y-NM 600（用于PET成像和受试者特异性剂量测定）和IV 90 Y-NM 600（治疗性放射性核素）的治疗诊断配对，向患有转移性黑色素瘤或骨肉瘤的伴侣犬的所有转移部位给予2戈伊免疫调节剂量。在一个犬亚组中，初步评估免疫学参数。免疫-放疗组合的组分单独或组合耐受性良好，仅导致一过性低级别（1或2）不良事件，未观察到剂量限制性事件。在受试者特异性剂量测定分析中，我们观察到接受联合给药的5只犬中有4只的86 Y-NM 600肿瘤：骨髓床剂量差异摄取≥2，这允许随后向肿瘤安全输送至少2戈伊90 Y-NM 600 TRT。治疗前和治疗后活检标本的NanoString基因表达谱和免疫组织化学提供了90 Y-NM 600 TRT对肿瘤微环境免疫调节的证据。已知在小鼠模型中对同系黑色素瘤具有活性的外照射放疗、瘤内免疫细胞因子和靶向放射性核素免疫放疗的组合在患有晚期自发性黑色素瘤或骨肉瘤的伴侣犬中是可行的且耐受良好，并且具有免疫调节潜力。目前正在进行进一步的研究，以评价这种免疫-放疗联合治疗的剂量依赖性免疫调节作用。
Murine syngeneic tumor models have revealed efficacious systemic antitumor responses following primary tumor in situ vaccination combined with targeted radionuclide therapy to secondary or metastatic tumors. Here we present studies on the safety and feasibility of this approach in a relevant translational companion dog model (n = 17 dogs) with advanced cancer. The three component of the combination immuno-radiotherapy approach were employed either separately or in combination in companion dogs with advanced stage cancer. In situ vaccination was achieved through the administration of hypofractionated external beam radiotherapy and intratumoral hu14.18-IL2 fusion immunocytokine injections to the index tumor. In situ vaccination was subsequently combined with targeted radionuclide therapy using a theranostic pairing of IV 86Y-NM600 (for PET imaging and subject-specific dosimetry) and IV 90Y-NM600 (therapeutic radionuclide) prescribed to deliver an immunomodulatory 2 Gy dose to all metastatic sites in companion dogs with metastatic melanoma or osteosarcoma. In a subset of dogs, immunologic parameters preliminarily assessed. The components of the immuno-radiotherapy combination were well tolerated either alone or in combination, resulting in only transient low grade (1 or 2) adverse events with no dose-limiting events observed. In subject-specific dosimetry analyses, we observed 86Y-NM600 tumor:bone marrow absorbed-dose differential uptakes ≥2 in 4 of 5 dogs receiving the combination, which allowed subsequent safe delivery of at least 2 Gy 90Y-NM600 TRT to tumors. NanoString gene expression profiling and immunohistochemistry from pre- and post-treatment biopsy specimens provide evidence of tumor microenvironment immunomodulation by 90Y-NM600 TRT. The combination of external beam radiotherapy, intratumoral immunocytokine, and targeted radionuclide immuno-radiotherapy known to have activity against syngeneic melanoma in murine models is feasible and well tolerated in companion dogs with advanced stage, spontaneously arising melanoma or osteosarcoma and has immunomodulatory potential. Further studies evaluating the dose-dependent immunomodulatory effects of this immuno-radiotherapy combination are currently ongoing.
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DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
通讯作者：
Demaria S
影响因子：
14.9
作者：
Geer LY;Marchler-Bauer A;Geer RC;Han L;He J;He S;Liu C;Shi W;Bryant SH
通讯作者：
Bryant SH
影响因子：
82.9
作者：
Formenti SC;Rudqvist NP;Golden E;Cooper B;Wennerberg E;Lhuillier C;Vanpouille-Box C;Friedman K;Ferrari de Andrade L;Wucherpfennig KW;Heguy A;Imai N;Gnjatic S;Emerson RO;Zhou XK;Zhang T;Chachoua A;Demaria S
通讯作者：
Demaria S
影响因子：
2.1
作者：
通讯作者：
--
影响因子：
3.9
作者：
HELFAND, SC;SOERGEL, SA;SONDEL, PM
通讯作者：
SONDEL, PM