TY - JOUR
T1 - [89Zr]ZrDFO-CR011 PET Correlates with Response to Glycoprotein Nonmetastatic Melanoma B–targeted Therapy in Triple-negative Breast Cancer
AU - Lee, Supum
AU - Cavaliere, Alessandra
AU - Gallezot, Jean Dominique
AU - Keler, Tibor
AU - Michelhaugh, Sharon K.
AU - Belitzky, Erika
AU - Liu, Michael
AU - Mulnix, Tim
AU - Maher, Stephen E.
AU - Bothwell, Alfred L.M.
AU - Li, Fangyong
AU - Phadke, Manali
AU - Mittal, Sandeep
AU - Marquez-Nostra, Bernadette
N1 - Funding Information:
We wish to thank the Mallinckrodt Institute of Radiology at Washington University for production and delivery of Zr-89 and Drs. Suxia Sun and Xianhong Xiang for their assistance with imaging and therapy experiments. This work was supported by the NIH grant R00CA201601.
Funding Information:
J.-D. Gallezot reports grants from NIH during the conduct of the study; grants from Siemens Healthineers outside the submitted work. T. Keler is an employee and stock holder in Celldex Therapeutics, Inc. A company involved in the development of agents described in this article. T. Mulnix reports grants from NIH R00CA201601 during the conduct of the study. A.L.M. Bothwell reports grants from Mary Kay Foundation and Eli Lilly Pharmacueticals during the conduct of the study; grants from Eli Lilly Pharmaceuticals outside the submitted work. F. Li reports personal fees from Yiviva Inc. outside the submitted work. B. Marquez-Nostra reports grants from NIH during the conduct of the study; grants from NIH outside the submitted work; and Celldex therapeutics provided the CR011 and CDX-011 antibodies for this work. No disclosures were reported by the other authors.
Publisher Copyright:
© 2022 American Association for Cancer Research.
PY - 2022/3
Y1 - 2022/3
N2 - There is a need for prognostic markers to select patients most likely to benefit from antibody–drug conjugate (ADC) therapy. We quantified the relationship between pretreatment PET imaging of glycoprotein nonmetastatic melanoma B (gpNMB) with 89Zr-labeled anti-gpNMB antibody ([89Zr]ZrDFO-CR011) and response to ADC therapy (CDX-011) in triple-negative breast cancer. First, we compared different PET imaging metrics and found that standardized uptake values (SUV) and tumor-to-heart SUV ratios were sufficient to delineate differences in radiotracer uptake in the tumor of four different cell- and patient-derived tumor models and achieved high standardized effect sizes. These tumor models with varying levels of gpNMB expression were imaged with [89Zr]ZrDFO-CR011 followed by treatment with a single bolus injection of CDX-011. The percent change in tumor volume relative to baseline (% CTV) was then correlated with SUVmean of [89Zr]ZrDFO-CR011 uptake in the tumor. All gpNMB-positive tumor models responded to CDX-011 over 6 weeks of treatment, except one patient-derived tumor regrew after 4 weeks of treatment. As expected, the gpNMB-negative tumor increased in volume by 130 59% at endpoint. The magnitude of pretreatment SUV had the strongest inverse correlation with the % CTV at 2–4 weeks after treatment with CDX-011 (Spearman r = -0.8). However, pretreatment PET imaging with [89Zr]ZrDFO-CR011 did not inform on which tumor types will regrow over time. Other methods will be needed to predict resistance to treatment.
AB - There is a need for prognostic markers to select patients most likely to benefit from antibody–drug conjugate (ADC) therapy. We quantified the relationship between pretreatment PET imaging of glycoprotein nonmetastatic melanoma B (gpNMB) with 89Zr-labeled anti-gpNMB antibody ([89Zr]ZrDFO-CR011) and response to ADC therapy (CDX-011) in triple-negative breast cancer. First, we compared different PET imaging metrics and found that standardized uptake values (SUV) and tumor-to-heart SUV ratios were sufficient to delineate differences in radiotracer uptake in the tumor of four different cell- and patient-derived tumor models and achieved high standardized effect sizes. These tumor models with varying levels of gpNMB expression were imaged with [89Zr]ZrDFO-CR011 followed by treatment with a single bolus injection of CDX-011. The percent change in tumor volume relative to baseline (% CTV) was then correlated with SUVmean of [89Zr]ZrDFO-CR011 uptake in the tumor. All gpNMB-positive tumor models responded to CDX-011 over 6 weeks of treatment, except one patient-derived tumor regrew after 4 weeks of treatment. As expected, the gpNMB-negative tumor increased in volume by 130 59% at endpoint. The magnitude of pretreatment SUV had the strongest inverse correlation with the % CTV at 2–4 weeks after treatment with CDX-011 (Spearman r = -0.8). However, pretreatment PET imaging with [89Zr]ZrDFO-CR011 did not inform on which tumor types will regrow over time. Other methods will be needed to predict resistance to treatment.
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U2 - 10.1158/1535-7163.MCT-21-0590
DO - 10.1158/1535-7163.MCT-21-0590
M3 - Article
C2 - 35027482
AN - SCOPUS:85125846577
VL - 21
SP - 440
EP - 447
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
SN - 1535-7163
IS - 3
ER -