CellSight Technologies Incorporated, San Francisco, California; and
CellSight Technologies Incorporated, San Francisco, California; and.
J Nucl Med. 2021 Jun 1;62(6):802-807. doi: 10.2967/jnumed.120.249078. Epub 2020 Nov 6.
Most clinical trials exploring various combinations of chemo- and immunotherapy rely on serial biopsy to provide information on immune response. The aim of this study was to assess the value of F-arabinosyl guanine (F-AraG) as a noninvasive tool that profiles tumors on the basis of the key player in adaptive antitumor response, CD8+ cells, and evaluates the immunomodulatory effects of chemotherapy. To evaluate the ability of F-AraG to report on the presence of CD8+ cells within the tumor microenvironment, we imaged a panel of syngeneic tumor models (MC38, CT26, LLC, A9F1, 4T1, and B16F10) and correlated the signal intensity with the number of lymphocytes found in the tumors. The capacity of F-AraG to detect immunomodulatory effects of chemotherapy was determined by longitudinal imaging of tumor-bearing mice (MC38 and A9F1) undergoing 2 types of chemotherapy: oxaliplatin/cyclophosphamide, shown to induce immunogenic cell death, and paclitaxel/carboplatin, reported to cause immunogenically silent tumor cell death. In the tumor panel, F-AraG revealed strikingly different uptake patterns resembling cancer-immune phenotypes observed in the clinic. A statistically significant correlation was found between the F-AraG signal and the number of PD-1-positive CD8+ cells isolated from the tumors ( = 0.528, < 0.0001). In the MC38 model, paclitaxel/carboplatin did not result in an appreciable change in signal after therapy (1.69 ± 0.25 vs. 1.50 ± 0.33 percentage injected dose per gram), but oxaliplatin/cyclophosphamide treatment led to close to a 2.4-fold higher F-AraG signal (1.20 ± 0.31 vs. 2.84 ± 0.93 percentage injected dose per gram). The statistically significant increase in signal after oxaliplatin/cyclophosphamide was also observed in the A9F1 model (0.95 ± 0.36 vs. 1.99 ± 0.54 percentage injected dose per gram). The ability of F-AraG PET to assess the location and function of CD8+ cells, as well immune activity within tumors after immune priming therapy, warrants further investigation into its utility for patient selection, evaluation of optimal time to deliver immunotherapies, and assessment of combinatorial therapies.
大多数探索化疗和免疫治疗各种组合的临床试验都依赖于连续活检，以提供关于免疫反应的信息。本研究的目的是评估 F-阿拉伯呋喃糖基鸟嘌呤 (F-AraG) 作为一种非侵入性工具的价值，该工具基于适应性抗肿瘤反应的关键参与者 CD8+细胞对肿瘤进行分析，并评估化疗的免疫调节作用。为了评估 F-AraG 报告肿瘤微环境中 CD8+细胞存在的能力，我们对一系列同源肿瘤模型（MC38、CT26、LLC、A9F1、4T1 和 B16F10）进行了成像，并将信号强度与肿瘤中发现的淋巴细胞数量相关联。通过对接受 2 种化疗的荷瘤小鼠（MC38 和 A9F1）进行纵向成像，确定了 F-AraG 检测化疗免疫调节作用的能力：奥沙利铂/环磷酰胺，已证明可诱导免疫原性细胞死亡，以及紫杉醇/卡铂，据报道可引起免疫沉默的肿瘤细胞死亡。在肿瘤面板中，F-AraG 揭示了截然不同的摄取模式，类似于临床中观察到的癌症-免疫表型。F-AraG 信号与从肿瘤中分离出的 PD-1 阳性 CD8+细胞数量之间存在显著的相关性（=0.528，<0.0001）。在 MC38 模型中，紫杉醇/卡铂治疗后信号没有明显变化（1.69±0.25 与 1.50±0.33 每克注射剂量百分比），但奥沙利铂/环磷酰胺治疗导致 F-AraG 信号接近 2.4 倍升高（1.20±0.31 与 2.84±0.93 每克注射剂量百分比）。奥沙利铂/环磷酰胺治疗后信号的统计学显著增加也在 A9F1 模型中观察到（0.95±0.36 与 1.99±0.54 每克注射剂量百分比）。F-AraG PET 评估 CD8+细胞的位置和功能以及免疫原性治疗后肿瘤内免疫活性的能力，需要进一步研究其在患者选择、评估最佳免疫治疗时机以及评估联合治疗方面的效用。
