Examining Immunotherapy Response Using Multiple Radiotracers.

Molecular imaging and biology (2020-02-02)
Julian L Goggi, Siddesh V Hartimath, Youyi Hwang, Yun Xuan Tan, Shivashankar Khanapur, Boominathan Ramasamy, Lingfan Jiang, Fui Fong Yong, Peter Cheng, Peng Wen Tan, Mohamed Ar Husaini, Tsz Ying Yuen, Beverly Jieu, Ann-Marie Chacko, Anis Larbi, Laurent Renia, Charles Johannes, Edward G Robins
ABSTRACT

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, [18F]FDG (a glucose analogue), [18F]FEPPA (a marker for macrophage activation), [18F]FB-IL2 (a marker for CD25+ cells) and [68Ga] 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. [18F]FDG, [18F]FEPPA and [18F]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, [68Ga] Ga-mNOTA-GZP showed good predictive ability and correlated well with changes in tumour-associated T cells, especially CD8+ T cells. [68Ga]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 [68Ga]Ga-mNOTA-GZP may allow for the reduction of unnecessary side effects while significantly improving patient management.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Methyl benzenesulfonate, 98%
Sigma-Aldrich
4-Phenoxypyridine, AldrichCPR

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