Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #01-02 Helios, Singapore, 138667, Singapore.
Singapore Immunology Network, A* STAR, 8A Biomedical Grove, Immunos, Singapore, 138648, Singapore.
Mol Imaging Biol. 2020 Aug;22(4):993-1002. doi: 10.1007/s11307-020-01477-w.
Cancer immunotherapy has shown huge potential in the fight against cancer, but only a small proportion of patients respond successfully to treatment. Non-invasive methods to stratify responders from non-responders are critically important as immune therapies are often associated with immune-related side effects. Currently, conventional clinical imaging modalities do not provide a useful measure of immune therapy efficacy. Sensitive imaging biomarkers that provide information about the tumoural microenvironment may provide useful insights allowing for improved patient management.
We have assessed the ability of a number of radiopharmaceuticals to non-invasively measure different aspects of the tumour microenvironment and correlated tumour uptake to immune therapy response in a syngeneic model of colon cancer, CT26-WT. Four radiopharmaceuticals, [F]FDG (a glucose analogue), [F]FEPPA (a marker for macrophage activation), [F]FB-IL2 (a marker for CD25 cells) and [Ga] Ga-mNOTA-GZP (a marker for granzyme B, the serine protease downstream effector of cytotoxic T cells), were assessed as potential biomarkers to help stratify response to PD-1 monotherapy or combined anti-PD1 and CLTA4 therapy in vivo correlating tumour uptake with changes in tumour-associated immune cell populations.
[F]FDG, [F]FEPPA and [F]FB-IL2 (a marker for CD25 cells) showed limited ability to determine therapy response and showed little correlation to tumour-associated immune cell changes. However, [Ga] Ga-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8 T cells.
[Ga]Ga-mNOTA-GZP uptake correlates well with changes in CD8 T cell populations supporting continued development of granzyme B-based imaging agents for stratification of response to immunotherapy. Early assessment of immunotherapy efficacy with [Ga]Ga-mNOTA-GZP may allow for the reduction of unnecessary side effects while significantly improving patient management.
癌症免疫疗法在抗击癌症方面显示出巨大的潜力，但只有一小部分患者对治疗成功作出反应。将应答者与无应答者进行分层的非侵入性方法非常重要，因为免疫疗法通常与免疫相关的副作用有关。目前，常规的临床成像方式并不能提供免疫治疗疗效的有用衡量标准。提供关于肿瘤微环境信息的敏感成像生物标志物可能会提供有用的见解，从而改善患者管理。
我们评估了许多放射性药物的能力，这些放射性药物可以非侵入性地测量肿瘤微环境的不同方面，并在结直肠癌细胞（CT26-WT）的同种异体模型中，将肿瘤摄取与免疫治疗反应相关联。评估了四种放射性药物，[F]FDG（葡萄糖类似物）、[F]FEPPA（巨噬细胞活化标志物）、[F]FB-IL2（CD25 细胞标志物）和[Ga]Ga-mNOTA-GZP（颗粒酶 B 的标志物，细胞毒性 T 细胞下游效应物丝氨酸蛋白酶），作为潜在的生物标志物，用于帮助分层 PD-1 单药治疗或联合抗 PD1 和 CLTA4 治疗的反应，将肿瘤摄取与肿瘤相关免疫细胞群的变化相关联。
[F]FDG、[F]FEPPA 和 [F]FB-IL2（CD25 细胞标志物）显示出确定治疗反应的有限能力，与肿瘤相关免疫细胞变化相关性较差。然而，[Ga]Ga-mNOTA-GZP 显示出良好的预测能力，与肿瘤相关 T 细胞（尤其是 CD8 T 细胞）的变化密切相关。
[Ga]Ga-mNOTA-GZP 的摄取与 CD8 T 细胞群的变化密切相关，支持继续开发基于颗粒酶 B 的成像剂，以分层免疫治疗的反应。用[Ga]Ga-mNOTA-GZP 对免疫治疗疗效进行早期评估，可能减少不必要的副作用，同时显著改善患者管理。
