Granzyme B PET Imaging of Immune Checkpoint Inhibitor Combinations in Colon Cancer Phenotypes
Granzyme B PET Imaging of Immune Checkpoint Inhibitor Combinations in Colon Cancer Phenotypes
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DOI：
10.1007/s11307-020-01519-3
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发表时间：
2020-07-23
影响因子：
3.1
通讯作者：
Robins, Edward G.
中科院分区：
文献类型：
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作者：
Goggi, J. L.;Tan, Y. X.;Robins, Edward G.
免疫检查点抑制剂（ICI）单药治疗和联合治疗方案正被积极寻求作为提高癌症患者持久缓解率的策略。然而，围绕联合治疗的生物学尚不清楚，可能会增加免疫介导的不良事件的可能性。通过非侵入性PET成像对ICI反应进行准确分层可能有助于确保在多种癌症表型中进行安全的治疗管理。我们评估了靶向颗粒酶B的氟标记肽[F-18]AlF-mNOTA-GZP在两种同基因结肠癌模型CT 26和MC 38中分层ICI反应的能力。在ICI单一治疗或与PD-1联合治疗后，[F-18]AlF-mNOTA-GZP的体内肿瘤摄取被表征并与肿瘤相关免疫细胞群的变化相关。结果[F-18]AlF-mNOTA-GZP显示出良好的预测能力，并与肿瘤相关T细胞，特别是CD 8 + T细胞的变化密切相关;然而，在CT 26和MC 38肿瘤中，对单药治疗或联合治疗的总体摄取和反应非常不同，这可能是由于MC 38肿瘤中MSI高表型所赋予的免疫刺激环境。结论[F-18]AlF-mNOTA-GZP摄取与CD 8 + T细胞群的变化密切相关，并且能够将肿瘤对作为单一疗法或组合施用的一系列ICI的反应分层。然而，示踪剂摄取可能会受到预先存在的表型异常的显着影响，可能会混淆数据解释。
Purpose Immune checkpoint inhibitor (ICI) monotherapy and combination regimens are being actively pursued as strategies to improve durable response rates in cancer patients. However, the biology surrounding combination therapies is not well understood and may increase the likelihood of immune-mediated adverse events. Accurate stratification of ICI response by non-invasive PET imaging may help ensure safe therapy management across a wide number of cancer phenotypes. Procedures We have assessed the ability of a fluorine-labelled peptide, [F-18]AlF-mNOTA-GZP, targeting granzyme B, to stratify ICI response in two syngeneic models of colon cancer, CT26 and MC38.In vivotumour uptake of [F-18]AlF-mNOTA-GZP following ICI monotherapy, or in combination with PD-1 was characterised and correlated with changes in tumour-associated immune cell populations. Results [F-18]AlF-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells; however, overall uptake and response to monotherapy or combination therapies was very different in the CT26 and MC38 tumours, likely due to the immunostimulatory environment imbued by the MSI-high phenotype in MC38 tumours. Conclusions [F-18]AlF-mNOTA-GZP uptake correlates well with changes in CD8+ T cell populations and is able to stratify tumour response to a range of ICIs administered as monotherapies or in combination. However, tracer uptake can be significantly affected by preexisting phenotypic abnormalities potentially confusing data interpretation.