title: 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.
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 a64Cu-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 of64Cu-MM-302 as part of a clinical trial of MM-302 plus trastuzumab with and without cyclophosphamide (NCT01304797).Results:Significant background uptake of64Cu-MM-302 was observed in liver and spleen. Tumor accumulation of64Cu-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 of64Cu-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, high64Cu-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.Clin Cancer Res; 23(15); 4190-202. ©2017 AACR.
authors.affiliation: Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts. hlee@merrimack.com.
authors.forename: Helen
authors.initials: H
authors.lastname: Lee
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Anthony F
authors.initials: AF
authors.lastname: Shields
authors.affiliation: Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Barry A
authors.initials: BA
authors.lastname: Siegel
authors.affiliation: Indiana University Melvin and Bren Simon Cancer Center, Indianapolis, Indiana.
authors.forename: Kathy D
authors.initials: KD
authors.lastname: Miller
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Ian
authors.initials: I
authors.lastname: Krop
authors.affiliation: Siteman Cancer Center, Washington University, St. Louis, Missouri.
authors.forename: Cynthia X
authors.initials: CX
authors.lastname: Ma
authors.affiliation: Yale Cancer Center, New Haven, Connecticut.
authors.forename: Patricia M
authors.initials: PM
authors.lastname: LoRusso
authors.affiliation: Helen Diller Family Comprehensive Cancer Center, San Francisco, California.
authors.forename: Pamela N
authors.initials: PN
authors.lastname: Munster
authors.affiliation: Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors.forename: Karen
authors.initials: K
authors.lastname: Campbell
authors.affiliation: Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gaddy
authors.affiliation: Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors.forename: Shannon C
authors.initials: SC
authors.lastname: Leonard
authors.affiliation: Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors.forename: Elena
authors.initials: E
authors.lastname: Geretti
authors.affiliation: Karmanos Cancer Institute, Detroit, Michigan.
authors.forename: Stephanie J
authors.initials: SJ
authors.lastname: Blocker
authors.affiliation: Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Kirpotin
authors.affiliation: Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors.forename: Victor
authors.initials: V
authors.lastname: Moyo
authors.affiliation: Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wickham
authors.affiliation: Merrimack Pharmaceuticals, Inc, Cambridge, Massachusetts.
authors.forename: Bart S
authors.initials: BS
authors.lastname: Hendriks
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D001859:Bone Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D001932:Brain Neoplasms / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology / Q000556:secondary; D001943:Breast Neoplasms / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000473:pathology; D002463:Cell Membrane Permeability / Q000187:drug effects / Q000528:radiation effects; D003301:Copper Radioisotopes / Q000008:administration & dosage / Q000737:chemistry; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000737:chemistry; D005260:Female; D006801:Humans; D008099:Liver / Q000000981:diagnostic imaging / Q000187:drug effects; D008875:Middle Aged; D053758:Nanoparticles / Q000008:administration & dosage* / Q000737:chemistry; D009362:Neoplasm Metastasis; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000737:chemistry; D000072078:Positron Emission Tomography Computed Tomography; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000097:blood; D013154:Spleen / Q000000981:diagnostic imaging / Q000473:pathology; D000068878:Trastuzumab / Q000008:administration & dosage
chemical_list: D003301:Copper Radioisotopes; D003520:Cyclophosphamide; D004317:Doxorubicin; D011092:Polyethylene Glycols; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C506643:liposomal doxorubicin; C508053:ERBB2 protein, human