Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity

• DOI: 10.1038/mt.2013.17
• Publication Date: 2013-02-19T13:43:33Z
• Authors: Cor HJ Lamers; Stefan Sleijfer; Sabine van Steenb...; Pascal van Elzakker; Brigitte van Krimpen; Corrien Groot; Arnold Vulto; Michael den Bakker; Egbert Oosterwijk; Reno Debets; Jan W Gratama
• Keywords: Pharmacology; 0303 health sciences; T-Lymphocytes; Gene Dosage; ONCOL 3: Translational research NCMLS 3: Tissue engineering and pathology; EMC MM-03-24-01; Flow Cytometry; Immunohistochemistry; Kidney Neoplasms; 3. Good health; 03 medical and health sciences; Treatment Outcome; EMC MM-03-86-08; Drug Discovery; Genetics; Molecular Medicine; Cytokines; Humans; EMC OR-01-34-01; EMC MM-03-86-01; Molecular Biology; Carcinoma, Renal Cell; Carbonic Anhydrases

Autologous T cells genetically modified to express a chimeric antibody receptor (CAR) against carboxy-anhydrase-IX (CAIX) were administered 12 patients with CAIX-expressing metastatic renal cell carcinoma (RCC). Patients treated in three cohorts maximum of 10 infusions total 0.2 2.1 × 109 CAR cells. CTC grade 2–4 liver enzyme disturbances occurred at the lowest doses, necessitating cessation treatment four out eight 1 and 2. Examination biopsies revealed CAIX expression on bile duct epithelium infiltration cells, including Subsequently pre-treated monoclonal (mAb) G250 prevent CAR-specific toxicity showed no toxicities indications for enhanced peripheral persistence. No clinical responses recorded. This report shows that CAIX-targeting exerted antigen-specific effects vivo induced dose applied, illustrating potency receptor-modified We provide in-patient proof observed "on-target" is antigen-directed can be prevented by blocking antigenic sites off-tumor organs allowing higher doses.