64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer

Helen Lee, Anthony F. Shields, Barry A. Siegel, Kathy Miller, Ian Krop, Cynthia X. Ma, Patricia M. Lorusso, Pamela N. Munster, Karen Campbell, Daniel F. Gaddy, Shannon C. Leonard, Elena Geretti, Stephanie J. Blocker, Dmitri B. Kirpotin, Victor Moyo, Thomas J. Wickham, Bart S. Hendriks

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Abstract

Purpose: Therapeutic nanoparticles are designed to deliver their drug payloads through enhanced permeability and retention (EPR) in solid tumors. The extent of EPR and its variability in human tumors is highly debated and has been proposed as an explanation for variable responses to therapeutic nanoparticles in clinical studies. Experimental Design: We assessed the EPR effect in patients using a 64Cu-labeled nanoparticle, 64Cu-MM-302 (64Cu-labeled HER2-targeted PEGylated liposomal doxorubicin), and imaging by PET/CT. Nineteen patients with HER2-positive metastatic breast cancer underwent 2 to 3 PET/CT scans postadministration of 64Cu-MM-302 as part of a clinical trial of MM-302 plus trastuzumab with and without cyclophosphamide (NCT01304797). Results: Significant background uptake of 64Cu-MM-302 was observed in liver and spleen. Tumor accumulation of 64Cu-MM-302 at 24 to 48 hours varied 35-fold (0.52–18.5 %ID/kg), including deposition in bone and brain lesions, and was independent of systemic plasma exposure. Computational analysis quantified rates of deposition and washout, indicating peak liposome deposition at 24 to 48 hours. Patients were classified on the basis of 64Cu-MM-302 lesion deposition using a cut-off point that is comparable with a response threshold in preclinical studies. In a retrospective exploratory analysis of patient outcomes relating to drug levels in tumor lesions, high 64Cu-MM-302 deposition was associated with more favorable treatment outcomes (HR = 0.42). Conclusions: These findings provide important evidence and quantification of the EPR effect in human metastatic tumors and support imaging nanoparticle deposition in tumors as a potential means to identify patients well suited for treatment with therapeutic nanoparticles.

Original languageEnglish (US)
Pages (from-to)4190-4202
Number of pages13
JournalClinical Cancer Research
Volume23
Issue number15
DOIs
StatePublished - Aug 1 2017

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Positron-Emission Tomography
Nanoparticles
Permeability
Breast Neoplasms
Neoplasms
Therapeutics
Liposomes
Pharmaceutical Preparations
Cyclophosphamide
Research Design
Spleen
Clinical Trials
Bone and Bones
Liver
Brain

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer. / Lee, Helen; Shields, Anthony F.; Siegel, Barry A.; Miller, Kathy; Krop, Ian; Ma, Cynthia X.; Lorusso, Patricia M.; Munster, Pamela N.; Campbell, Karen; Gaddy, Daniel F.; Leonard, Shannon C.; Geretti, Elena; Blocker, Stephanie J.; Kirpotin, Dmitri B.; Moyo, Victor; Wickham, Thomas J.; Hendriks, Bart S.

In: Clinical Cancer Research, Vol. 23, No. 15, 01.08.2017, p. 4190-4202.

Research output: Contribution to journalArticle

Lee, H, Shields, AF, Siegel, BA, Miller, K, Krop, I, Ma, CX, Lorusso, PM, Munster, PN, Campbell, K, Gaddy, DF, Leonard, SC, Geretti, E, Blocker, SJ, Kirpotin, DB, Moyo, V, Wickham, TJ & Hendriks, BS 2017, '64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer', Clinical Cancer Research, vol. 23, no. 15, pp. 4190-4202. https://doi.org/10.1158/1078-0432.CCR-16-3193
Lee, Helen ; Shields, Anthony F. ; Siegel, Barry A. ; Miller, Kathy ; Krop, Ian ; Ma, Cynthia X. ; Lorusso, Patricia M. ; Munster, Pamela N. ; Campbell, Karen ; Gaddy, Daniel F. ; Leonard, Shannon C. ; Geretti, Elena ; Blocker, Stephanie J. ; Kirpotin, Dmitri B. ; Moyo, Victor ; Wickham, Thomas J. ; Hendriks, Bart S. / 64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer. In: Clinical Cancer Research. 2017 ; Vol. 23, No. 15. pp. 4190-4202.
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abstract = "Purpose: Therapeutic nanoparticles are designed to deliver their drug payloads through enhanced permeability and retention (EPR) in solid tumors. The extent of EPR and its variability in human tumors is highly debated and has been proposed as an explanation for variable responses to therapeutic nanoparticles in clinical studies. Experimental Design: We assessed the EPR effect in patients using a 64Cu-labeled nanoparticle, 64Cu-MM-302 (64Cu-labeled HER2-targeted PEGylated liposomal doxorubicin), and imaging by PET/CT. Nineteen patients with HER2-positive metastatic breast cancer underwent 2 to 3 PET/CT scans postadministration of 64Cu-MM-302 as part of a clinical trial of MM-302 plus trastuzumab with and without cyclophosphamide (NCT01304797). Results: Significant background uptake of 64Cu-MM-302 was observed in liver and spleen. Tumor accumulation of 64Cu-MM-302 at 24 to 48 hours varied 35-fold (0.52–18.5 {\%}ID/kg), including deposition in bone and brain lesions, and was independent of systemic plasma exposure. Computational analysis quantified rates of deposition and washout, indicating peak liposome deposition at 24 to 48 hours. Patients were classified on the basis of 64Cu-MM-302 lesion deposition using a cut-off point that is comparable with a response threshold in preclinical studies. In a retrospective exploratory analysis of patient outcomes relating to drug levels in tumor lesions, high 64Cu-MM-302 deposition was associated with more favorable treatment outcomes (HR = 0.42). Conclusions: These findings provide important evidence and quantification of the EPR effect in human metastatic tumors and support imaging nanoparticle deposition in tumors as a potential means to identify patients well suited for treatment with therapeutic nanoparticles.",
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T1 - 64Cu-MM-302 positron emission tomography quantifies variability of enhanced permeability and retention of nanoparticles in relation to treatment response in patients with metastatic breast cancer

AU - Lee, Helen

AU - Shields, Anthony F.

AU - Siegel, Barry A.

AU - Miller, Kathy

AU - Krop, Ian

AU - Ma, Cynthia X.

AU - Lorusso, Patricia M.

AU - Munster, Pamela N.

AU - Campbell, Karen

AU - Gaddy, Daniel F.

AU - Leonard, Shannon C.

AU - Geretti, Elena

AU - Blocker, Stephanie J.

AU - Kirpotin, Dmitri B.

AU - Moyo, Victor

AU - Wickham, Thomas J.

AU - Hendriks, Bart S.

PY - 2017/8/1

Y1 - 2017/8/1

N2 - Purpose: Therapeutic nanoparticles are designed to deliver their drug payloads through enhanced permeability and retention (EPR) in solid tumors. The extent of EPR and its variability in human tumors is highly debated and has been proposed as an explanation for variable responses to therapeutic nanoparticles in clinical studies. Experimental Design: We assessed the EPR effect in patients using a 64Cu-labeled nanoparticle, 64Cu-MM-302 (64Cu-labeled HER2-targeted PEGylated liposomal doxorubicin), and imaging by PET/CT. Nineteen patients with HER2-positive metastatic breast cancer underwent 2 to 3 PET/CT scans postadministration of 64Cu-MM-302 as part of a clinical trial of MM-302 plus trastuzumab with and without cyclophosphamide (NCT01304797). Results: Significant background uptake of 64Cu-MM-302 was observed in liver and spleen. Tumor accumulation of 64Cu-MM-302 at 24 to 48 hours varied 35-fold (0.52–18.5 %ID/kg), including deposition in bone and brain lesions, and was independent of systemic plasma exposure. Computational analysis quantified rates of deposition and washout, indicating peak liposome deposition at 24 to 48 hours. Patients were classified on the basis of 64Cu-MM-302 lesion deposition using a cut-off point that is comparable with a response threshold in preclinical studies. In a retrospective exploratory analysis of patient outcomes relating to drug levels in tumor lesions, high 64Cu-MM-302 deposition was associated with more favorable treatment outcomes (HR = 0.42). Conclusions: These findings provide important evidence and quantification of the EPR effect in human metastatic tumors and support imaging nanoparticle deposition in tumors as a potential means to identify patients well suited for treatment with therapeutic nanoparticles.

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