Julian L Goggi1, Siddesh V Hartimath2, Youyi Hwang3, Yun Xuan Tan2, Shivashankar Khanapur2, Boominathan Ramasamy2, Lingfan Jiang2, Fui Fong Yong2, Peter Cheng2, Peng Wen Tan2, Mohamed Ar Husaini2, Tsz Ying Yuen4, Beverly Jieu4, Ann-Marie Chacko5, Anis Larbi4, Laurent Renia3, Charles Johannes6, Edward G Robins2,7. 1. Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #01-02 Helios, Singapore, 138667, Singapore. julian_goggi@sbic.a-star.edu.sg. 2. Singapore Bioimaging Consortium, Agency for Science, Technology and Research (A*STAR), 11 Biopolis Way, #01-02 Helios, Singapore, 138667, Singapore. 3. Singapore Immunology Network, A* STAR, 8A Biomedical Grove, Immunos, Singapore, 138648, Singapore. 4. Institute of Chemical and Engineering Sciences (ICES), A*STAR, 8 Biomedical Grove, #07, Neuros, Singapore, 138665, Singapore. 5. Laboratory for Translational and Molecular Imaging (LTMI), Cancer and Stem Cell Biology Programme, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore. 6. p53 Laboratory, A*STAR, 8A Biomedical Grove, #06-04/05, Neuros/Immunos, Singapore, 138665, Singapore. 7. Clinical Imaging Research Centre, 14 Medical Drive, #B1-01, Yong Loo Lin School of Medicine, National University of Singapore, 21 Lower Kent Ridge Rd, Singapore, 117599, Singapore.
Abstract
PURPOSE: 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. PROCEDURES: 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. RESULTS: [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. CONCLUSIONS: [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.
PURPOSE: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. PROCEDURES: 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. RESULTS:[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. CONCLUSIONS:[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.
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Authors: Siddesh V Hartimath; Boominathan Ramasamy; Tan Yun Xuan; Tang Jun Rong; Shivashankar Khanapur; Peter Cheng; You Yi Hwang; Edward G Robins; Julian L Goggi Journal: Pharmaceutics Date: 2022-01-08 Impact factor: 6.321