title: Cyclophosphamide-Mediated Tumor Priming for Enhanced Delivery and Antitumor Activity of HER2-Targeted Liposomal Doxorubicin (MM-302).
abstract: Given the bulky nature of nanotherapeutics relative to small molecules, it is hypothesized that effective tumor delivery and penetration are critical barriers to their clinical activity. HER2-targeted PEGylated liposomal doxorubicin (MM-302, HER2-tPLD) is an antibody-liposomal drug conjugate designed to deliver doxorubicin to HER2-overexpressing cancer cells while limiting uptake into nontarget cells. In this work, we demonstrate that the administration and appropriate dose sequencing of cyclophosphamide can improve subsequent MM-302 delivery and enhance antitumor activity in preclinical models without negatively affecting nontarget tissues, such as the heart and skin. We demonstrate that this effect is critically dependent on the timing of cyclophosphamide administration. Furthermore, the effect was found to be unique to cyclophosphamide and related analogues, and not shared by other agents, such as taxanes or eribulin, under the conditions examined. Analysis of the cyclophosphamide-treated tumors suggests that the mechanism for improved MM-302 delivery involves the induction of tumor cell apoptosis, reduction of overall tumor cell density, substantial lowering of interstitial fluid pressure, and increasing vascular perfusion. The novel dosing strategy for cyclophosphamide described herein is readily translatable to standard clinical regimens, represents a potentially significant advance in addressing the drug delivery challenge, and may have broad applicability for nanomedicines. This work formed the basis for clinical evaluation of cyclophosphamide for improving liposome deposition as part of an ongoing phase I clinical trial of MM-302 in HER2-positive metastatic breast cancer.
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts. egeretti@merrimackpharma.com.
authors.forename: Elena
authors.initials: E
authors.lastname: Geretti
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Shannon Curtis
authors.initials: SC
authors.lastname: Leonard
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Nancy
authors.initials: N
authors.lastname: Dumont
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Helen
authors.initials: H
authors.lastname: Lee
authors.affiliation: STTARR, Spatio-Temporal Targeting and Amplification of Radiation Response Program, Toronto, Ontario, Canada.
authors.forename: Jinzi
authors.initials: J
authors.lastname: Zheng
authors.affiliation: STTARR, Spatio-Temporal Targeting and Amplification of Radiation Response Program, Toronto, Ontario, Canada.
authors.forename: Raquel
authors.initials: R
authors.lastname: De Souza
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Daniel F
authors.initials: DF
authors.lastname: Gaddy
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Espelin
authors.affiliation: STTARR, Spatio-Temporal Targeting and Amplification of Radiation Response Program, Toronto, Ontario, Canada.
authors.forename: David A
authors.initials: DA
authors.lastname: Jaffray
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Victor
authors.initials: V
authors.lastname: Moyo
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Ulrik B
authors.initials: UB
authors.lastname: Nielsen
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Wickham
authors.affiliation: Merrimack Pharmaceuticals, Cambridge, Massachusetts.
authors.forename: Bart S
authors.initials: BS
authors.lastname: Hendriks
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000008:administration & dosage / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy / Q000378:metabolism*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000494:pharmacology*; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D005260:Female; D006801:Humans; D007069:Ifosfamide / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D011092:Polyethylene Glycols / Q000008:administration & dosage; D049268:Positron-Emission Tomography; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors*; D014057:Tomography, X-Ray Computed; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D000903:Antibiotics, Antineoplastic; D003520:Cyclophosphamide; D004317:Doxorubicin; D007069:Ifosfamide; D011092:Polyethylene Glycols; D018719:Erb-b2 Receptor Tyrosine Kinases; C506643:liposomal doxorubicin