title: Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity.
abstract: Autologous T cells genetically modified to express a chimeric antibody receptor (CAR) against carboxy-anhydrase-IX (CAIX) were administered to 12 patients with CAIX-expressing metastatic renal cell carcinoma (RCC). Patients were treated in three cohorts with a maximum of 10 infusions of a total of 0.2 to 2.1 × 10(9) CAR T cells. CTC grade 2-4 liver enzyme disturbances occurred at the lowest CAR T cell doses, necessitating cessation of treatment in four out of eight patients in cohorts 1 and 2. Examination of liver biopsies revealed CAIX expression on bile duct epithelium with infiltration of T cells, including CAR T cells. Subsequently four patients were pre-treated with CAIX monoclonal antibody (mAb) G250 to prevent CAR-specific toxicity and showed no liver toxicities and indications for enhanced peripheral T cell persistence. No clinical responses were recorded. This report shows that CAIX-targeting CAR T cells exerted antigen-specific effects in vivo and induced liver toxicity at the lowest dose of 0.2 × 10(9) T cells applied, illustrating the potency of receptor-modified T cells. We provide in-patient proof that the observed "on-target" toxicity is antigen-directed and can be prevented by blocking antigenic sites in off-tumor organs and allowing higher T cell doses.
authors: Department of Medical Oncology, Erasmus University Medical Center - Daniel den Hoed Cancer Center, Rotterdam, The Netherlands. c.lamers@erasmusmc.nl
authors: Cor Hj
authors: CH
authors: Lamers
authors: Stefan
authors: S
authors: Sleijfer
authors: Sabine
authors: S
authors: van Steenbergen
authors: Pascal
authors: P
authors: van Elzakker
authors: Brigitte
authors: B
authors: van Krimpen
authors: Corrien
authors: C
authors: Groot
authors: Arnold
authors: A
authors: Vulto
authors: Michael
authors: M
authors: den Bakker
authors: Egbert
authors: E
authors: Oosterwijk
authors: Reno
authors: R
authors: Debets
authors: Jan W
authors: JW
authors: Gratama
mesh_terms: D002256:Carbonic Anhydrases / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000276:immunology*; D016207:Cytokines / Q000378:metabolism; D005434:Flow Cytometry; D018628:Gene Dosage / Q000235:genetics; D006801:Humans; D007150:Immunohistochemistry; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D002256:Carbonic Anhydrases