Department of Radiology, Stanford University, Stanford, California.
Molecular Imaging Program at Stanford (MIPS), Stanford University, Stanford, California.
Clin Cancer Res. 2021 Apr 1;27(7):1932-1940. doi: 10.1158/1078-0432.CCR-20-2725. Epub 2021 Jan 6.
Therapeutic checkpoint inhibitors on tumor-infiltrating lymphocytes (TIL) are being increasingly utilized in the clinic. The T-cell immunoreceptor with Ig and ITIM domains (TIGIT) is an inhibitory receptor expressed on T and natural killer cells. The TIGIT signaling pathway is an alternative target for checkpoint blockade to current PD-1/CTLA-4 strategies. Elevated TIGIT expression in the tumor microenvironment correlates with better therapeutic responses to anti-TIGIT therapies in preclinical models. Therefore, quantifying TIGIT expression in tumors is necessary for determining whether a patient may respond to anti-TIGIT therapy. PET imaging of TIGIT expression on TILs can therefore aid diagnosis and in monitoring therapeutic responses.
Antibody-based TIGIT imaging radiotracers were developed with the PET radionuclides copper-64 (Cu) and zirconium-89 (Zr). characterization of the imaging probes was followed by evaluation in both xenografts and syngeneic tumor models in mouse.
Two anti-TIGIT probes were developed and exhibited immunoreactivity of >72%, serum stability of >95%, and specificity for TIGIT with both mouse TIGIT-expressing HeLa cells and -activated primary splenocytes. , the Zr-labeled probe demonstrated superior contrast than the Cu probe due to Zr's longer half-life matching the TIGIT antibody's pharmacokinetics. The Zr probe was used to quantify TIGIT expression on TILs in B16 melanoma in immunocompetent mice and confirmed by flow cytometry.
This study develops and validates novel TIGIT-specific Cu and Zr PET probes for quantifying TIGIT expression on TILs for diagnosis of patient selection for anti-TIGIT therapies.
肿瘤浸润淋巴细胞（TIL）上的治疗性检查点抑制剂在临床上的应用越来越多。T 细胞免疫受体含有免疫球蛋白和 ITIM 结构域（TIGIT）是一种在 T 细胞和自然杀伤细胞上表达的抑制性受体。TIGIT 信号通路是目前 PD-1/CTLA-4 策略的另一个检查点阻断靶点。肿瘤微环境中 TIGIT 表达的升高与临床前模型中抗 TIGIT 治疗的更好治疗反应相关。因此，定量肿瘤中的 TIGIT 表达对于确定患者是否对抗 TIGIT 治疗有反应是必要的。TIL 上 TIGIT 表达的 PET 成像因此可以辅助诊断和监测治疗反应。
开发了基于抗体的 TIGIT 成像放射性示踪剂，使用 PET 放射性核素铜-64（Cu）和锆-89（Zr）。对成像探针进行了表征，随后在小鼠的异种移植和同源肿瘤模型中进行了评估。
开发了两种抗 TIGIT 探针，其免疫反应性>72%，血清稳定性>95%，对 TIGIT 具有特异性，包括表达小鼠 TIGIT 的 HeLa 细胞和激活的原代脾细胞。此外，Zr 标记的探针由于 Zr 的半衰期比 TIGIT 抗体的药代动力学更长，因此具有比 Cu 探针更高的对比度。该 Zr 探针用于定量免疫功能正常的小鼠中 B16 黑色素瘤中 TIL 上的 TIGIT 表达，并通过流式细胞术进行了验证。
本研究开发并验证了新型 TIGIT 特异性 Cu 和 Zr PET 探针，用于定量 TIL 上的 TIGIT 表达，以诊断患者选择抗 TIGIT 治疗。
