Purpose: Immunotherapy efficacy data on appendiceal cancer from clinical trials does not exist, due to appendiceal cancer incidence of 0.97 per 100,000. The goal of this study was to preclinically explore the application of immunotherapy in treating appendiceal cancer in a personalized organoid model. Experimental Design: Patient tumor organoids (PTO) were fabricated using unsorted tumor cells with and without enrichment with patient-matched immune components derived from peripheral blood leukocytes, spleen, or lymph nodes [immune-enhanced PTOs (iPTO)]. Organoids were cultured for 7 days, followed by treatment with immunotherapy (pembrolizumab, ipilimumab, nivolumab), and assessed for treatment efficacy. Results: Between September 2019 and May 2021, 26 patients were enrolled in the study. Successful testing was conducted in 19 of 26 (73.1%) patients, with 13 of 19 (68.4%) and 6 of 19 (31.6%) patients having low-grade appendiceal (LGA) and high-grade appendiceal (HGA) primaries, respectively. Immunotherapy response, with increased expression of granzyme B and cleaved caspase 3 and decreased expression of CK20 and ATP activity, was exhibited in 4 of 19 (21.1%) pembrolizumab-treated and 2 of 19 (10.5%) nivolumab-treated iPTOs. Post-immunotherapy cellular viability, in responding HGA organoids to pembrolizumab, decreased to less than 15% ( P < 0.05). LGA iPTO treatment responses were observed in pembrolizumab and nivolumab, with an 8%–47.4% ( P < 0.05) viability compared with controls. Ipilimumab showed no efficacy in the examined cohort. Conclusions: Immunotherapy shows measurable efficacy in appendiceal cancer organoids. Information derived from immunocompetent organoids may be applied in selecting patients for clinical trial enrollment in rare diseases where preclinical models of disease are lacking.

中文翻译：

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阑尾癌个体化免疫治疗疗效临床前研究的类器官平台：可行性研究

目的：由于阑尾癌发病率为 0.97/100,000，因此不存在来自临床试验的阑尾癌免疫治疗疗效数据。本研究的目的是在临床前探索免疫疗法在个性化类器官模型中治疗阑尾癌的应用。实验设计：患者肿瘤类器官 (PTO) 是使用未分类的肿瘤细胞制造的，该肿瘤细胞富含或不富含来自外周血白细胞、脾脏或淋巴结的患者匹配的免疫成分 [免疫增强型 PTO (iPTO)]。将类器官培养 7 天，然后用免疫疗法（pembrolizumab、ipilimumab、nivolumab）治疗，并评估治疗效果。结果：2019 年 9 月至 2021 年 5 月期间，共有 26 名患者参加了该研究。26 人中有 19 人成功进行了测试（73. 1%) 患者，其中 19 例中的 13 例 (68.4%) 和 19 例中的 6 例 (31.6%) 分别具有低级别阑尾 (LGA) 和高级别阑尾 (HGA) 初级。在 19 个（21.1%）pembrolizumab 治疗的 iPTO 和 19 个（10.5%）nivolumab 治疗的 iPTO 中，有 4 个（21.1%）表现出免疫治疗反应，颗粒酶 B 和切割的 caspase 3 表达增加，CK20 和 ATP 活性表达降低。免疫治疗后，HGA 类器官对 pembrolizumab 的反应中细胞活力下降到不到 15% ( P < 0.05)。在 pembrolizumab 和 nivolumab 中观察到 LGA iPTO 治疗反应，与对照组相比，存活率为 8%–47.4% ( P < 0.05)。Ipilimumab 在检查的队列中没有显示出疗效。结论：免疫疗法在阑尾癌类器官中显示出可测量的疗效。