Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: Clinical evaluation and management of on-target toxicity
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.
|Keywords||CD4+ T lymphocyte, CD8+ T lymphocyte, T lymphocyte, antigen expression, article, cancer survival, cholangitis, clinical article, controlled study, cytokine production, cytolysis, drug blood level, flow cytometry, histopathology, human, human cell, human tissue, interferon production, kidney metastasis, liver biopsy, liver metastasis, liver toxicity, multiple cycle treatment, overall survival|
|Persistent URL||dx.doi.org/10.1038/mt.2013.17, hdl.handle.net/1765/40589|
Lamers, C.H.J, Sleijfer, S, van Steenbergen, S.C.L, van Elzakker, P.M.M.L, van Krimpen, B.A, Groot, C, … Gratama, J.W. (2013). Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: Clinical evaluation and management of on-target toxicity. Molecular Therapy, 21(4), 904–912. doi:10.1038/mt.2013.17