title: Tumor Regression and Delayed Onset Toxicity Following B7-H4 CAR T Cell Therapy.
abstract: B7-H4 protein is frequently overexpressed in ovarian cancer. Here, we engineered T cells with novel B7-H4-specific chimeric antigen receptors (CARs) that recognized both human and murine B7-H4 to test the hypothesis that B7-H4 CAR T cell therapy can be applied safely in preclinical models. B7-H4 CAR T cells specifically secreted IFN-γ and lysed B7-H4(+) targets. In vivo, B7-H4 CAR T cells displayed antitumor reactivity against B7-H4(+) human ovarian tumor xenografts. Unexpectedly, B7-H4 CAR T cell treatment reproducibly showed delayed, lethal toxicity 6-8 weeks after therapy. Comprehensive assessment of murine B7-H4 protein distribution uncovered expression in ductal and mucosal epithelial cells in normal tissues. Postmortem analysis revealed the presence of widespread histologic lesions that correlated with B7-H4(+) expression, and were inconsistent with graft versus host disease. Lastly, expression patterns of B7-H4 protein in normal human tissue were comparable to distribution in mice, advancing our understanding of B7-H4. We conclude that B7-H4 CAR therapy mediates control of cancer outgrowth. However, long-term engraftment of B7-H4 CAR T cells mediates lethal, off-tumor toxicity that is likely due to wide expression of B7-H4 in healthy mouse organs. This model system provides a unique opportunity for preclinical evaluation of safety approaches that limit CAR-mediated toxicity after tumor destruction in vivo.
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, Philadelphia, Pennsylvania, USA; Department of Obstetrics and Gynecology, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Jenessa B
authors.initials: JB
authors.lastname: Smith
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, Philadelphia, Pennsylvania, USA; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.
authors.forename: Evripidis
authors.initials: E
authors.lastname: Lanitis
authors.affiliation: Department of Obstetrics and Gynecology, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Ludwig Institute for Cancer Research, University of Lausanne, Lausanne, Switzerland.
authors.forename: Denarda
authors.initials: D
authors.lastname: Dangaj
authors.affiliation: Department of Pathobiology, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania, USA.
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Buza
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, Philadelphia, Pennsylvania, USA; Department of Obstetrics and Gynecology, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
authors.forename: Mathilde
authors.initials: M
authors.lastname: Poussin
authors.affiliation: Department of Obstetrics and Gynecology, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; Lancaster General Health, Penn Medicine, Lancaster, Pennsylvania, USA.
authors.forename: Caitlin
authors.initials: C
authors.lastname: Stashwick
authors.affiliation: Department of Obstetrics and Gynecology, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA; SRI Biosciences, Menlo Park, California, USA.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Scholler
authors.affiliation: Department of Pathology and Laboratory Medicine, Center for Cellular Immunotherapies, Philadelphia, Pennsylvania, USA; Department of Obstetrics and Gynecology, Ovarian Cancer Research Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA. Electronic address: poda@mail.med.upenn.edu.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Powell
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D064987:Cell- and Tissue-Based Therapy / Q000379:methods*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051379:Mice; D010051:Ovarian Neoplasms / Q000276:immunology / Q000628:therapy*; D011946:Receptors, Antigen / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000637:transplantation; D016896:Treatment Outcome; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1 / Q000276:immunology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011946:Receptors, Antigen; D060907:V-Set Domain-Containing T-Cell Activation Inhibitor 1