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, [¹⁸F]AlF-mNOTA-GZP, targeting granzyme B, to stratify ICI response in two syngeneic models of colon cancer, CT26 and MC38. In vivo tumour uptake of [¹⁸F]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

[¹⁸F]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

[¹⁸F]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.

中文翻译：

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结肠癌表型中免疫检查点抑制剂组合的颗粒酶 B PET 成像。

目的

免疫检查点抑制剂（ICI）单一疗法和联合疗法正在积极寻求作为提高癌症患者持久缓解率的策略。然而，联合疗法的生物学原理尚不清楚，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对多种癌症表型进行安全的治疗管理。

程序

^{我们评估了靶向颗粒酶B的氟标记肽[ 18} F]AlF-mNOTA-GZP在两种同基因结肠癌模型CT26和MC38中分层ICI反应的能力。ICI单一疗法或与PD-1组合后[ ^{18 F]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

[ ¹⁸ F]AlF- m NOTA-GZP 显示出良好的预测能力，并且与肿瘤相关 T 细胞，尤其是 CD8+ T 细胞的变化具有良好的相关性；然而，CT26 和 MC38 肿瘤中对单一疗法或联合疗法的总体吸收和反应非常不同，这可能是由于 MC38 肿瘤中 MSI 高表型所带来的免疫刺激环境所致。

结论

[ ¹⁸ F]AlF- m NOTA-GZP 摄取与 CD8+ T 细胞群的变化密切相关，并且能够对作为单一疗法或组合施用的一系列 ICI 的肿瘤反应进行分层。然而，示踪剂的摄取可能会受到先前存在的表型异常的显着影响，可能会混淆数据解释。