title: Immune activation and a 9-year ongoing complete remission following CD40 antibody therapy and metastasectomy in a patient with metastatic melanoma.
abstract: Direct immune activation via agonistic mAbs is a potentially complementary approach to therapeutic blockade of inhibitory immune receptors in cancer. Here, we provide genetic analysis of the immunologic consequences associated with the use of an agonistic CD40 mAb in a patient with metastatic melanoma who responded, underwent a single metastasectomy, and then achieved a complete remission ongoing for more than 9 years after starting therapy. Tumor microenvironment after immunotherapy was associated with proinflammatory modulations and emergence of a de novo T-cell repertoire as detected by next-generation sequencing of T-cell receptors (TCR) in the tumor and blood. The de novo T-cell repertoire identified in the posttreatment metastasectomy sample was also present-and in some cases expanded-in the circulation years after completion of therapy. Comprehensive study of this "exceptional responder" highlights the emerging potential of direct immune agonists in the next wave of cancer immunotherapies and a potential role for TCR deep sequencing in cancer immune assessment.
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: David L
authors.initials: DL
authors.lastname: Bajor
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia. Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Xu
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia. Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Drew A
authors.initials: DA
authors.lastname: Torigian
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia. Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Mick
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia.
authors.forename: Laura R
authors.initials: LR
authors.lastname: Garcia
authors.affiliation: Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia.
authors.forename: Lee P
authors.initials: LP
authors.lastname: Richman
authors.affiliation: Adaptive Biotechnologies, Seattle, Washington.
authors.forename: Cindy
authors.initials: C
authors.lastname: Desmarais
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Nathanson
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Lynn M
authors.initials: LM
authors.lastname: Schuchter
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia. Department of Pathology, Perelman School of Medicine, University of Pennsylvania, Philadelphia.
authors.forename: Michael
authors.initials: M
authors.lastname: Kalos
authors.affiliation: Abramson Cancer Center, University of Pennsylvania, Philadelphia. Abramson Family Cancer Research Institute, University of Pennsylvania, Philadelphia. Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia. rhv@exchange.upenn.edu.
authors.forename: Robert H
authors.initials: RH
authors.lastname: Vonderheide
mesh_terms: D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D019013:CD40 Antigens / Q000276:immunology*; D002469:Cell Separation; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000276:immunology; D059146:Metastasectomy; D008875:Middle Aged; D012074:Remission Induction; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000276:immunology; D059016:Tumor Microenvironment / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D019013:CD40 Antigens; C518149:selicrelumab