The Effectiveness of Checkpoint Inhibitor Combinations and Administration Timing Can Be Measured by Granzyme B PET Imaging

Abstract

Purpose: The lack of a timely and reliable measure of response to cancer immunotherapy has confounded understanding of mechanisms of resistance and subsequent therapeutic advancement. We hypothesized that PET imaging of granzyme B using a targeted peptide, GZP, could be utilized for early response assessment across many checkpoint inhibitor combinations, and that GZP uptake could be compared between therapeutic regimens and dosing schedules as an early biomarker of relative efficacy. Experimental Design: Two models, MC38 and CT26, were treated with a series of checkpoint inhibitors. GZP PET imaging was performed to assess tumoral GZP uptake, and tumor volume changes were subsequently monitored to determine response. The average GZP PET uptake and response of each treatment group were correlated to evaluate the utility of GZP PET for comparing therapeutic efficacy. Results: In both tumor models, GZP PET imaging was highly accurate for predicting response, with 93% sensitivity and 94% negative predictive value. Mean tumoral GZP signal intensity of treatment groups linearly correlated with percent response across all therapies and schedules. Moreover, GZP PET correctly predicted that sequential dose scheduling of PD-1 and CTLA-4 targeted therapies demonstrates comparative efficacy to concurrent administration. Conclusions: Granzyme B quantification is a highly sensitive and specific early measure of therapeutic efficacy for checkpoint inhibitor regimens. This work provides evidence that GZP PET imaging may be useful for rapid assessment of therapeutic efficacy in the context of clinical trials for both novel drugs as well as dosing regimens.

Immunotherapy by Immune Checkpoint Inhibitors and Nuclear Medicine Imaging: Current and Future Applications

“…Another interesting target of immune Cancers 2020, 12, 371 8 of 23 response could be the protease granzyme B (GZP), which is secreted by cytotoxic CD8+ and has a key role for immune-induced apoptosis [43]. In preclinical tumor models, a highly specific peptide PET imaging agent for GZP was predictive of the response to immune-checkpoint inhibitors, with high signal tumors responding to therapy and with 93% sensitivity and 94% negative predictive value [44]. Clinical studies have yet to be done.…”

Role of medical imaging for immune checkpoint blockade therapy: From response assessment to prognosis prediction

“…Despite the tremendous potential of antibody‐based tracers, they have slow blood clearance that leads to long waiting time (eg, several days) between imaging scan and tracer injection, which prevents the clinical transformation of the molecular imaging. In this setting, a number of protein‐ or peptide‐based radiotracers have been fabricated to compensate the pitfalls of the antibody‐based probes . For example, Trotte et al developed a 18 F‐labeled affibody ligand that can effectively detect PD‐L1 expression in xenograft tumors by PET imaging, with preferable specificity, fast blood clearance, and low normal tissue uptake except nephridia .…”

“…In this setting, a number of protein-or peptide-based radiotracers have been fabricated to compensate the pitfalls of the antibody-based probes. [84][85][86][87][88][89][90][91] For example, Trotte et al developed a 18 F-labeled affibody ligand that can effectively detect PD-L1 expression in xenograft tumors by PET imaging, with preferable specificity, fast blood clearance, and low normal tissue uptake except nephridia. 85 Larimer et al demonstrated that granzyme B PET imaging might serve as an effective biomarker for predicting responses to immunotherapy in human tumor xenograft models.…”

“…85 Larimer et al demonstrated that granzyme B PET imaging might serve as an effective biomarker for predicting responses to immunotherapy in human tumor xenograft models. 89,90 In summary, molecular imaging demonstrated enormous potential to produce a large number of biomarkers. Visualization of PD-L1 expression in vivo is a hot spot in the latest researches on molecular imaging in immunotherapy.…”

ICOS Is an Indicator of T-cell–Mediated Response to Cancer Immunotherapy

“…To predict response at the earliest stages, biomarkers of immune cell activation are requisite. Upon successful immunotherapy, immune cells are activated and then home to the tumor tissue where they can (25,26), have shown promising results both for response monitoring and assessment of therapeutic strength. However, these secreted biomarkers pose challenges for imaging including half-life and dilution.…”