Granzyme B PET Imaging as a Predictive Biomarker of Immunotherapy Response.
Benjamin Larimer,Eric Wehrenberg-Klee,Frank Dubois,Anila J. Mehta,Taylor Kalomeris,Keith T. Flaherty,Genevieve M. Boland,Umar Mahmood +7 more
TLDR
G granzyme B PET imaging can serve as a quantitatively useful predictive biomarker for efficacious responses to cancer immunotherapy, and is a clear candidate for clinical application.Abstract:
While cancer immunotherapy can produce dramatic responses, only a minority of patients respond to treatment. Reliable response biomarkers are needed to identify responders, and conventional imaging modalities have not proved adequate. Here, we provide a preclinical proof of concept for the use of granzyme B, a downstream effector of tumoral cytotoxic T cells, as an early biomarker for tumors responding to immunotherapy. We designed novel PET imaging probes for the murine and human granzyme B isoforms that specifically and quantitatively bind granzyme B. Immunotherapy-treated mice were imaged prior to therapy-induced tumor volume reduction. Imaging distinguished treated responders from nonresponders with excellent predictive ability. To assess the clinical value of a granzyme B imaging paradigm, biopsy specimens from melanoma patients on checkpoint inhibitor therapy were analyzed. A marked differential in granzyme B expression was observed between treated responders and nonresponders. Additionally, our human probe was able to specifically detect granzyme B expression in human samples, providing a clear candidate for clinical application. Overall, our results suggest granzyme B PET imaging can serve as a quantitatively useful predictive biomarker for efficacious responses to cancer immunotherapy. Cancer Res; 77(9); 2318-27. ©2017 AACR.read more
Citations
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Targeting apoptosis in cancer therapy
TL;DR: The main pathways that regulate apoptosis as well as other signalling pathways that interact with them are presented, highlighting actionable molecular targets for anticancer therapy and an overview of therapeutic agents exploiting apoptosis currently in clinical translation and known mechanisms of resistance to these agents are provided.
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ImmunoPET: Concept, Design, and Applications
TL;DR: The latest immuno PET imaging strategies and their preclinical and clinical applications are presented and current conjugation strategies that can be leveraged to develop next-generation immunoPET probes are emphasized.
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Near-infrared fluorescent macromolecular reporters for real-time imaging and urinalysis of cancer immunotherapy
TL;DR: In this paper, renal-clearable near-infrared (NIR) fluorescent macromolecular reporters are synthesized to specifically detect an immunoactivation-related biomarker (granzyme B) for real-time evaluation of cancer immunotherapy.
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Imaging of Cancer Immunotherapy: Current Approaches and Future Directions.
TL;DR: The background and current status of cancer immunotherapy are summarized, and the current methods for imaging evaluations of immune-related responses and toxicities are reviewed along with their limitations and pitfalls.
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Imaging activated T cells predicts response to cancer vaccines
Israt S. Alam,Aaron T. Mayer,Idit Sagiv-Barfi,Kezheng Wang,Ophir Vermesh,Debra K. Czerwinski,Emily M. Johnson,Michelle L. James,Ronald Levy,Sanjiv S. Gambhir +9 more
TL;DR: A PET tracer that enabled noninvasive and longitudinal imaging of OX40, a cell-surface marker of T cell activation, indicates that 64Cu-DOTA-AbOX40 is a promising candidate for monitoring clinical cancer immunotherapy strategies.
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Apoptosis by death factor.
TL;DR: This work was supported in part by Grants-in-Aid from the Ministry of Education, Science, and Culture of Japan and by a Research Grant from the Princess Takamatsu Cancer Research Fund, and performed in part through Special Coordination Funds of the Science and Technology Agency of the Japanese Government.
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