Larimer Benjamin M, Wehrenberg-Klee Eric, Dubois Frank, Mehta Anila, Kalomeris Taylor, Flaherty Keith, Boland Genevieve, Mahmood Umar
Athinoula A. Martinos Center for Biomedical Imaging, Department of Radiology, Massachusetts General Hospital, Boston, Massachusetts.
Department of Medicine, Harvard Medical School, Boston, Massachusetts.
Cancer Res. 2017 May 1;77(9):2318-2327. doi: 10.1158/0008-5472.CAN-16-3346.
While cancer immunotherapy can produce dramatic responses, only a minority of patients respond to treatment. Reliable response biomarkers are needed to identify responders, and conventional imaging modalities have not proved adequate. Here, we provide a preclinical proof of concept for the use of granzyme B, a downstream effector of tumoral cytotoxic T cells, as an early biomarker for tumors responding to immunotherapy. We designed novel PET imaging probes for the murine and human granzyme B isoforms that specifically and quantitatively bind granzyme B. Immunotherapy-treated mice were imaged prior to therapy-induced tumor volume reduction. Imaging distinguished treated responders from nonresponders with excellent predictive ability. To assess the clinical value of a granzyme B imaging paradigm, biopsy specimens from melanoma patients on checkpoint inhibitor therapy were analyzed. A marked differential in granzyme B expression was observed between treated responders and nonresponders. Additionally, our human probe was able to specifically detect granzyme B expression in human samples, providing a clear candidate for clinical application. Overall, our results suggest granzyme B PET imaging can serve as a quantitatively useful predictive biomarker for efficacious responses to cancer immunotherapy. .
虽然癌症免疫疗法能产生显著疗效，但只有少数患者对治疗有反应。需要可靠的反应生物标志物来识别有反应的患者，而传统的成像方式尚未证明足够有效。在此，我们为使用颗粒酶B（肿瘤细胞毒性T细胞的下游效应物）作为对免疫疗法有反应的肿瘤的早期生物标志物提供了临床前概念验证。我们设计了针对小鼠和人类颗粒酶B同工型的新型PET成像探针，它们能特异性且定量地结合颗粒酶B。在免疫疗法诱导肿瘤体积缩小之前，对接受免疫疗法治疗的小鼠进行成像。成像能够以出色的预测能力区分治疗有反应者和无反应者。为评估颗粒酶B成像模式的临床价值，对接受检查点抑制剂治疗的黑色素瘤患者的活检标本进行了分析。在治疗有反应者和无反应者之间观察到颗粒酶B表达存在显著差异。此外，我们的人类探针能够特异性检测人类样本中的颗粒酶B表达，为临床应用提供了一个明确的候选物。总体而言，我们的结果表明颗粒酶B PET成像可作为对癌症免疫疗法有效反应的定量有用预测生物标志物。
