GPC2 antibody–drug conjugate reprograms the neuroblastoma immune milieu to enhance macrophage-driven therapies

BackgroundAntibody–drug conjugates (ADCs) that deliver cytotoxic drugs to tumor cells have emerged as an effective and safe anticancer therapy. ADCs may induce immunogenic cell death (ICD) to promote additional endogenous antitumor immune responses. Here, we characterized the immunomodulatory proper...

Full description

Saved in:

Bibliographic Details
Published in:	Journal for immunotherapy of cancer Vol. 10; no. 12; p. e004704
Main Authors:	Pascual-Pasto, Guillem, McIntyre, Brendan, Shraim, Rawan, Buongervino, Samantha N, Erbe, Amy K, Zhelev, Doncho V, Sadirova, Shakhnozakhon, Giudice, Anna M, Martinez, Daniel, Garcia-Gerique, Laura, Dimitrov, Dimiter S, Sondel, Paul M, Bosse, Kristopher R
Format:	Journal Article
Language:	English
Published:	England BMJ Publishing Group Ltd 01-12-2022 BMJ Publishing Group LTD BMJ Publishing Group
Series:	Original research
Subjects:	Animals Antigens Cancer CD47 Antigen Clinical/Translational Cancer Immunotherapy Glypicans Humans Immunoconjugates - pharmacology Immunoconjugates - therapeutic use Immunotherapy Macrophages Mice Neuroblastoma Neuroblastoma - drug therapy Pediatrics Tumor Microenvironment Antigens Pediatrics Neuroblastoma Macrophages Immunotherapy
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	BackgroundAntibody–drug conjugates (ADCs) that deliver cytotoxic drugs to tumor cells have emerged as an effective and safe anticancer therapy. ADCs may induce immunogenic cell death (ICD) to promote additional endogenous antitumor immune responses. Here, we characterized the immunomodulatory properties of D3-GPC2-PBD, a pyrrolobenzodiazepine (PBD) dimer-bearing ADC that targets glypican 2 (GPC2), a cell surface oncoprotein highly differentially expressed in neuroblastoma.MethodsADC-mediated induction of ICD was studied in GPC2-expressing murine neuroblastomas in vitro and in vivo. ADC reprogramming of the neuroblastoma tumor microenvironment was profiled by RNA sequencing, cytokine arrays, cytometry by time of flight and flow cytometry. ADC efficacy was tested in combination with macrophage-driven immunoregulators in neuroblastoma syngeneic allografts and human patient-derived xenografts.ResultsThe D3-GPC2-PBD ADC induced biomarkers of ICD, including neuroblastoma cell membrane translocation of calreticulin and heat shock proteins (HSP70/90) and release of high-mobility group box 1 and ATP. Vaccination of immunocompetent mice with ADC-treated murine neuroblastoma cells promoted T cell-mediated immune responses that protected animals against tumor rechallenge. ADC treatment also reprogrammed the tumor immune microenvironment to a proinflammatory state in these syngeneic neuroblastoma models, with increased tumor trafficking of activated macrophages and T cells. In turn, macrophage or T-cell inhibition impaired ADC efficacy in vivo, which was alternatively enhanced by both CD40 agonist and CD47 antagonist antibodies. In human neuroblastomas, the D3-GPC2-PBD ADC also induced ICD and promoted tumor phagocytosis by macrophages, which was further enhanced when blocking CD47 signaling in vitro and in vivo.ConclusionsWe elucidated the immunoregulatory properties of a GPC2-targeted ADC and showed robust efficacy of combination immunotherapies in diverse neuroblastoma preclinical models.
Bibliography:	Original research ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	2051-1426 2051-1426
DOI:	10.1136/jitc-2022-004704