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- Title
Treatment of Metastatic Renal Cell Carcinoma With CAIX CAR-engineered T cells: Clinical Evaluation and Management of On-target Toxicity.
- Authors
Lamers, Cor HJ; Sleijfer, Stefan; van Steenbergen, Sabine; van Elzakker, Pascal; van Krimpen, Brigitte; Groot, Corrien; Vulto, Arnold; den Bakker, Michael; Oosterwijk, Egbert; Debets, Reno; Gratama, Jan W
- 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 × 109 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 × 109 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.
- Subjects
T cells; CHIMERISM; IMMUNOGLOBULINS; RENAL cell carcinoma; MONOCLONAL antibodies; ANTIGENS
- Publication
Molecular Therapy, 2013, Vol 21, Issue 4, p904
- ISSN
1525-0016
- Publication type
Article
- DOI
10.1038/mt.2013.17