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 SUV_max of primary tumors (SUV_max-t), SUV_max of metastatic lymph nodes (SUV_max-LN), and SUV_max 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 TLR_tumor and TBR_tumor and for metastatic lymph nodes as TLR_LN and TBR_LN, 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 SUV_max-t, TLR_tumor, TBR_tumor, SUV_max-LN, and TBR_LN 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 SUV_max-t, TBR_tumor, TLR_tumor, SUV_max-LN, TLR_LN, and TBR_LN was 0.886, 0.866, 0.746, 0.772, 0.648, and 0.731, respectively. The threshold of SUV_max-t was 2.05, and its sensitivity and specificity were 81.0% and 84.2%, respectively. In addition, multivariate logistic regression indicated that TBR_tumor 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.

在几种恶性肿瘤中，只有有限数量的患者对免疫检查点抑制剂有反应。预测和监测对这些抑制物的反应代表了未满足的临床需求。在这里，我们开发了一种靶向颗粒酶 B 的 PET/CT 探针，[⁶⁸Ga]Ga-NOTA-Gly-Gly-Gly-Ile-Glu-Pro-Asp-CHO （GSI），旨在研究它是否可以用于监测免疫检查点抑制剂在治疗过程早期的效果。方法：在 2 或 3 个周期的免疫治疗后，招募了 72 名胃癌患者 （III-IV 期） 进行 [⁶⁸Ga]Ga-NOTA-GSI PET/CT 成像，其中 40 名患者被纳入最终分析。测量原发肿瘤的 SUV_max （SUV_max-t） 、转移性淋巴结的 SUV_max （SUV_max-LN） 和正常组织 （肝脏和血池） 的 SUV_max，原发性肿瘤的靶肝背景比 （TLR） 和靶血背景比 （TBR） 表示为 TLR_肿瘤和 TBR_肿瘤，转移性淋巴结表示为 TLR_LN 和 TBR_LN分别。根据 RECIST 1.1 版，在全程治疗后 1 周内评估治疗反应。Wilcoxon 秩和检验用于比较反应者和无反应者之间的 PET/CT 参数。采用受试者工作特征曲线分析评价 [⁶⁸Ga]Ga-NOTA-GSI PET/CT 参数识别反应者的诊断效能。小于 0.05 的双尾 P 值被认为具有统计学意义。结果：我们发现 SUV_max-t 、 TLR_肿瘤、 TBR_肿瘤、 SUV_max-LN 和 TBR_LN 在反应者中高于无反应者 （2.49 ± 0。58 vs. 1.55 ± 0.48，P = 0.000; 2.24 ± 0.48 对 1.74 ± 0.67，P = 0.007; 1.38 ± 0.43 对 0.90 ± 0.23，P = 0.000; 2.24 ± 0.99 对比 1.42 ± 0.55，P = 0.003; 和 1.28 ± 0.68 对 0.83 ± 0.32，分别为 P = 0.012）。根据受试者工作特征曲线分析，SUV_max-t 、 TBR_肿瘤、 TLR_肿瘤、 SUV_max-LN、 TLR_LN和 TBR_LN 的曲线下面积分别为 0.886 、 0.866 、 0.746 、 0.772 、 0.648 和 0.731。SUV_max-t 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 logistic 回归表明 TBR_肿瘤是治疗反应的独立预测因子 （P = 0.03）。结论：我们的结果表明，[⁶⁸Ga]Ga-NOTA-GSI PET/CT 是预测胃癌患者对联合免疫治疗的早期反应的一种有前途的工具。