title: IAP antagonists induce anti-tumor immunity in multiple myeloma.
abstract: The cellular inhibitors of apoptosis (cIAP) 1 and 2 are amplified in about 3% of cancers and have been identified in multiple malignancies as being potential therapeutic targets as a result of their role in the evasion of apoptosis. Consequently, small-molecule IAP antagonists, such as LCL161, have entered clinical trials for their ability to induce tumor necrosis factor (TNF)-mediated apoptosis of cancer cells. However, cIAP1 and cIAP2 are recurrently homozygously deleted in multiple myeloma (MM), resulting in constitutive activation of the noncanonical nuclear factor (NF)-κB pathway. To our surprise, we observed robust in vivo anti-myeloma activity of LCL161 in a transgenic myeloma mouse model and in patients with relapsed-refractory MM, where the addition of cyclophosphamide resulted in a median progression-free-survival of 10 months. This effect was not a result of direct induction of tumor cell death, but rather of upregulation of tumor-cell-autonomous type I interferon (IFN) signaling and a strong inflammatory response that resulted in the activation of macrophages and dendritic cells, leading to phagocytosis of tumor cells. Treatment of a MM mouse model with LCL161 established long-term anti-tumor protection and induced regression in a fraction of the mice. Notably, combination of LCL161 with the immune-checkpoint inhibitor anti-PD1 was curative in all of the treated mice.
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Marta
authors.identifier: 0000-0002-4024-8225
authors.initials: M
authors.lastname: Chesi
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Noweeda N
authors.initials: NN
authors.lastname: Mirza
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Victoria M
authors.initials: VM
authors.lastname: Garbitt
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Meaghen E
authors.initials: ME
authors.lastname: Sharik
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Amylou C
authors.initials: AC
authors.lastname: Dueck
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Yan W
authors.initials: YW
authors.lastname: Asmann
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: Ilseyar
authors.initials: I
authors.lastname: Akhmetzyanova
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Heidi E
authors.initials: HE
authors.lastname: Kosiorek
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Arianna
authors.initials: A
authors.lastname: Calcinotto
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Riggs
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Niamh
authors.initials: N
authors.lastname: Keane
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Ahmann
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Kevin M
authors.initials: KM
authors.lastname: Morrison
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Rafael
authors.initials: R
authors.lastname: Fonseca
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Martha Q
authors.initials: MQ
authors.lastname: Lacy
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: David
authors.initials: D
authors.lastname: Dingli
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Shaji K
authors.initials: SK
authors.lastname: Kumar
authors.affiliation: Department of Medicine, Mayo Clinic Florida, Jacksonville, Florida, USA.
authors.forename: Sikander
authors.initials: S
authors.lastname: Ailawadhi
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Angela
authors.initials: A
authors.lastname: Dispenzieri
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Francis
authors.initials: F
authors.lastname: Buadi
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Morie A
authors.initials: MA
authors.lastname: Gertz
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: Craig B
authors.initials: CB
authors.lastname: Reeder
authors.affiliation: Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA.
authors.forename: Yi
authors.initials: Y
authors.lastname: Lin
authors.affiliation: Department of Medicine, Mayo Clinic Florida, Jacksonville, Florida, USA.
authors.forename: Asher A
authors.initials: AA
authors.lastname: Chanan-Khan
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: A Keith
authors.initials: AK
authors.lastname: Stewart
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, New York, New York, USA.
authors.forename: David
authors.initials: D
authors.lastname: Fooksman
authors.affiliation: Department of Medicine, Mayo Clinic Arizona, Scottsdale, Arizona, USA.
authors.forename: P Leif
authors.identifier: 0000-0003-1523-7388
authors.initials: PL
authors.lastname: Bergsagel
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D003520:Cyclophosphamide / Q000494:pharmacology; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000037:antagonists & inhibitors*; D007370:Interferon Type I / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008875:Middle Aged; D009101:Multiple Myeloma / Q000188:drug therapy* / Q000276:immunology; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy* / Q000276:immunology; D010587:Phagocytosis / Q000187:drug effects / Q000276:immunology; D013844:Thiazoles / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D051034:Inhibitor of Apoptosis Proteins; D007370:Interferon Type I; C574246:LCL161; D013844:Thiazoles; D003520:Cyclophosphamide