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Noninvasive interrogation of CD8+ T cell effector function for monitoring early tumor responses to immunotherapy
The Journal of Clinical Investigation ( IF 15.9 ) Pub Date : 2022 , DOI: 10.1172/jci161065
Haoyi Zhou 1 , Yanpu Wang 1 , Hongchuang Xu 2 , Xiuling Shen 3 , Ting Zhang 1 , Xin Zhou 3 , Yuwen Zeng 1 , Kui Li 1 , Li Zhang 4 , Hua Zhu 3 , Xing Yang 2 , Nan Li 3 , Zhi Yang 3 , Zhaofei Liu 1
Affiliation  

Accurately identifying patients who respond to immunotherapy remains clinically challenging. A noninvasive method that can longitudinally capture information about immune cell function and assist in the early assessment of tumor responses is highly desirable for precision immunotherapy. Here, we show that PET imaging using a granzyme B–targeted radiotracer named 68Ga-grazytracer, could noninvasively and effectively predict tumor responses to immune checkpoint inhibitors and adoptive T cell transfer therapy in multiple tumor models. 68Ga-grazytracer was designed and selected from several radiotracers based on non-aldehyde peptidomimetics, and exhibited excellent in vivo metabolic stability and favorable targeting efficiency to granzyme B secreted by effector CD8+ T cells during immune responses. 68Ga-grazytracer permitted more sensitive discrimination of responders and nonresponders than did 18F-fluorodeoxyglucose, distinguishing between tumor pseudoprogression and true progression upon immune checkpoint blockade therapy in mouse models with varying immunogenicity. In a preliminary clinical trial with 5 patients, no adverse events were observed after 68Ga-grazytracer injection, and clinical responses in cancer patients undergoing immunotherapy were favorably correlated with 68Ga-grazytracer PET results. These results highlight the potential of 68Ga-grazytracer PET to enhance the clinical effectiveness of granzyme B secretion–related immunotherapies by supporting early response assessment and precise patient stratification in a noninvasive and longitudinal manner.

中文翻译:

CD8+ T 细胞效应功能的非侵入性检测用于监测肿瘤对免疫治疗的早期反应

准确识别对免疫疗法有反应的患者在临床上仍然具有挑战性。一种可以纵向捕获有关免疫细胞功能的信息并有助于早期评估肿瘤反应的非侵入性方法对于精准免疫治疗来说是非常可取的。在这里,我们展示了使用名为68 Ga-grazytracer的颗粒酶 B 靶向放射性示踪剂的 PET 成像可以无创且有效地预测肿瘤对免疫检查点抑制剂的反应和多种肿瘤模型中的过继性 T 细胞转移治疗。68 Ga-grazytracer是基于非醛类肽模拟物从多种放射性示踪剂中设计和筛选出来的,表现出优异的体内代谢稳定性和对效应CD8 +分泌的颗粒酶B的良好靶向效率。免疫反应过程中的 T 细胞。68 Ga-grazytracer 允许比18 F-氟脱氧葡萄糖更敏感地区分反应者和无反应者,在具有不同免疫原性的小鼠模型中区分肿瘤假性进展和免疫检查点阻断治疗后的真正进展。在 5 名患者的初步临床试验中, 68 Ga-grazytracer 注射后未观察到不良事件,接受免疫治疗的癌症患者的临床反应与68 Ga-grazytracer PET 结果有利相关。这些结果突出了68Ga-grazytracer PET 通过以无创和纵向方式支持早期反应评估和精确的患者分层,提高颗粒酶 B 分泌相关免疫疗法的临床有效性。
更新日期:2022-08-16
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