Granzyme B PET/CT Imaging Evaluates Early Response to Immunotherapy in Gastric Cancer.

Qiufang Liu, Xiaoping Xu, Ziyi Yang, Jianping Zhang, Jindian Li, Ying Qiao, Silong Hu, Xiaosheng Liu, Weijian Guo, Shaoli Song
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Abstract

In several malignancies, only a limited number of patients respond to immune checkpoint inhibitors. Predicting and monitoring responses to these inhibitors represent an unmet clinical need. Here, we developed a PET/CT probe targeting granzyme B, [68Ga]Ga-NOTA-Gly-Gly-Gly-Ile-Glu-Pro-Asp-CHO (GSI), and aimed to investigate whether it can be used to monitor the effects of immune checkpoint inhibitors early in the course of therapy. Methods: Seventy-two patients with gastric cancer (stages III-IV) were recruited for [68Ga]Ga-NOTA-GSI PET/CT imaging after 2 or 3 cycles of the immunotherapy, and 40 patients were included in the final analysis. The SUVmax of primary tumors (SUVmax-t), SUVmax of metastatic lymph nodes (SUVmax-LN), and SUVmax of normal tissues (liver and blood pool) were measured, and their target-to-liver background ratio (TLR) and target-to-blood background ratio (TBR) were denoted for primary tumors as TLRtumor and TBRtumor and for metastatic lymph nodes as TLRLN and TBRLN, respectively. The treatment responses were assessed within 1 wk after full-course treatment according to RECIST version 1.1. Wilcoxon rank-sum tests were used to compare the PET/CT parameters between responders and nonresponders. Receiver operating characteristic curve analysis was used to assess the diagnostic efficacy of [68Ga]Ga-NOTA-GSI PET/CT parameters in identifying responders. Two-tailed P value of less than 0.05 was considered statistically significant. Results: We found that SUVmax-t, TLRtumor, TBRtumor, SUVmax-LN, and TBRLN were higher in responders than in nonresponders (2.49 ± 0.58 vs. 1.55 ± 0.48, P = 0.000; 2.24 ± 0.48 vs. 1.74 ± 0.67, P = 0.007; 1.38 ± 0.43 vs. 0.90 ± 0.23, P = 0.000; 2.24 ± 0.99 vs. 1.42 ± 0.55, P = 0.003; and 1.28 ± 0.68 vs. 0.83 ± 0.32, P = 0.012, respectively). According to receiver operating characteristic curve analysis, the area under the curve for SUVmax-t, TBRtumor, TLRtumor, SUVmax-LN, TLRLN, and TBRLN was 0.886, 0.866, 0.746, 0.772, 0.648, and 0.731, respectively. The threshold of SUVmax-t was 2.05, and its sensitivity and specificity were 81.0% and 84.2%, respectively. In addition, multivariate logistic regression indicated that TBRtumor was an independent predictor of treatment response (P = 0.03). Conclusion: Our results indicated that [68Ga]Ga-NOTA-GSI PET/CT is a promising tool for predicting early response to combined immunotherapy in gastric cancer patients.

Granzyme B PET/CT 成像评估胃癌患者对免疫疗法的早期反应
在几种恶性肿瘤中,只有少数患者对免疫检查点抑制剂有反应。预测和监测对这些抑制剂的反应是一项尚未满足的临床需求。在此,我们开发了一种靶向颗粒酶B的PET/CT探针--[68Ga]Ga-NOTA-Gly-Gly-Ile-Glu-Pro-Asp-CHO(GSI),旨在研究它是否可用于在治疗早期监测免疫检查点抑制剂的效果。研究方法招募72例胃癌患者(III-IV期),在接受2或3个周期的免疫治疗后进行[68Ga]Ga-DOTA-GSI PET/CT成像,40例患者纳入最终分析。测量原发肿瘤的SUVmax(SUVmax-t)、转移淋巴结的SUVmax(SUVmax-LN)和正常组织(肝脏和血池)的SUVmax,原发肿瘤的靶肝背景比(TLR)和靶血背景比(TBR)分别记为TLRtumor和TBRtumor,转移淋巴结的靶肝背景比(TLRLN)和靶血背景比(TBRLN)分别记为TLRLN和TBRLN。治疗反应根据 RECIST 1.1 版在全疗程治疗后 1 周内进行评估。采用 Wilcoxon 秩和检验比较有反应者和无反应者的 PET/CT 参数。接收者操作特征曲线分析用于评估[68Ga]Ga-DOTA-GSI PET/CT 参数在确定应答者方面的诊断效果。双尾 P 值小于 0.05 视为具有统计学意义。结果:我们发现,应答者的 SUVmax-t、TLRtumor、TBRtumor、SUVmax-LN 和 TBRLN 均高于非应答者(2.49 ± 0.58 vs. 1.55 ± 0.48,P = 0.000;2.24 ± 0.48 vs. 1.74 ± 0.67,P = 0.007;分别为 1.38 ± 0.43 vs. 0.90 ± 0.23,P = 0.000;2.24 ± 0.99 vs. 1.42 ± 0.55,P = 0.003;以及 1.28 ± 0.68 vs. 0.83 ± 0.32,P = 0.012)。根据接收者操作特征曲线分析,SUVmax-t、TBRtumor、TLRtumor、SUVmax-LN、TLRLN 和 TBRLN 的曲线下面积分别为 0.886、0.866、0.746、0.772、0.648 和 0.731。SUVmax-t的阈值为2.05,其敏感性和特异性分别为81.0%和84.2%。此外,多变量逻辑回归表明,TBRtumor 是治疗反应的独立预测因子(P = 0.03)。结论我们的研究结果表明,[68Ga]Ga-DOTA-GSI PET/CT 是预测胃癌患者对联合免疫疗法早期反应的有效工具。
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