title: A GRP78-Directed Monoclonal Antibody Recaptures Response in Refractory Multiple Myeloma with Extramedullary Involvement.
abstract: OBJECTIVE
  Glucose-regulated protein (GRP) 78 is overexpressed in multiple myeloma, and both its surface expression and its biologic significance as key sensor of the unfolded protein response make GRP78 an ideal candidate for immunotherapeutic intervention. The monoclonal antibody PAT-SM6 targets surface GRP78 and leads to disease stabilization when used as single agent in a clinical trial. In this article, we evaluated expression of GRP78 in relapsed-refractory disease and explored PAT-SM6 therapy in combination regimens.
  
  
  METHODS
  GRP78 expression was immunohistochemically analyzed during disease progression and development of drug resistance throughout different stages of multiple myeloma. Activity of PAT-SM6 was evaluated in combination with anti-multiple myeloma agents lenalidomide, bortezomib, and dexamethasone in vitro Finally, we report on a multiple myeloma patient with relapsed-refractory disease treated with PAT-SM6 in combination with bortezomib and lenalidomide.
  
  
  RESULTS
  Although sGRP78 expression was present at all stages, it increased with disease progression and was even strongly elevated in patients with drug-resistant and extramedullary disease. Pretreatment with dexamethasone as well as dual combination of PAT-SM6/lenalidomide further increased sGRP78 expression and consecutively showed synergistic anti-multiple myeloma effects with PAT-SM6 in proliferation assays. As proof of concept, a 62-year-old male with triple resistant multiple myeloma treated with PAT-SM6, bortezomib, and lenalidomide experienced partial remission of both intra- and extramedullary lesions.
  
  
  CONCLUSIONS
  PAT-SM6 therapy in combination regimens showed efficacy in relapsed-refractory multiple myeloma. Clin Cancer Res; 22(17); 4341-9. ©2016 AACR.
authors.affiliation: Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany. rasche_l@ukw.de LRasche@uams.edu.
authors.forename: Leo
authors.initials: L
authors.lastname: Rasche
authors.affiliation: Myelomax, Nantes, France.
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Menoret
authors.affiliation: Patrys Ltd., Melbourne, Australia.
authors.forename: Valentina
authors.initials: V
authors.lastname: Dubljevic
authors.affiliation: Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Eline
authors.initials: E
authors.lastname: Menu
authors.affiliation: Department of Hematology and Immunology, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: Karin
authors.initials: K
authors.lastname: Vanderkerken
authors.affiliation: Department of Nuclear Medicine, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Constantin
authors.initials: C
authors.lastname: Lapa
authors.affiliation: Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinbrunn
authors.affiliation: Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Manik
authors.initials: M
authors.lastname: Chatterjee
authors.affiliation: Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Knop
authors.affiliation: Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Düll
authors.affiliation: Patrys Ltd., Melbourne, Australia.
authors.forename: Deanne L
authors.initials: DL
authors.lastname: Greenwood
authors.affiliation: Patrys Ltd., Melbourne, Australia.
authors.forename: Frank
authors.initials: F
authors.lastname: Hensel
authors.affiliation: Institute of Pathology, University of Würzburg, Germany, and Comprehensive Cancer Center Mainfranken (CCCMF), Würzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Rosenwald
authors.affiliation: Department of Internal Medicine II, University Hospital of Würzburg, Würzburg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Einsele
authors.affiliation: Institute of Pathology, University of Würzburg, Germany, and Comprehensive Cancer Center Mainfranken (CCCMF), Würzburg, Germany.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Brändlein
mesh_terms: D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000074322:Antineoplastic Agents, Immunological / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D000091342:Endoplasmic Reticulum Chaperone BiP; D015870:Gene Expression; D006360:Heat-Shock Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology*; D009367:Neoplasm Staging; D012008:Recurrence; D019233:Retreatment
chemical_list: D000911:Antibodies, Monoclonal; D000074322:Antineoplastic Agents, Immunological; D000091342:Endoplasmic Reticulum Chaperone BiP; C000717247:HSPA5 protein, human; D006360:Heat-Shock Proteins