Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity.

By C. Lamers, S. Sleijfer, S. V. van Steenbergen, P. van Elzakker, B. V. van Krimpen, C. Groot, A. Vulto, M. D. den Bakker, E. Oosterwijk, R. Debets and 1 more. Molecular Therapy, 2013

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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.

Subfields: Biomedical Engineering, Genetics, Oncology

View Paper: https://www.semanticscholar.org/paper/cf64c6b987fce8e9d6db70a95f2ff6b06c4de658

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Citations in the corpus

TRUCKs: the fourth generation of CARs (2015, background): “The severity of clinical symptoms correlated with tumor burden and CAR T-cell dose [14,22,23].”
Toxicities of chimeric antigen receptor T cells: recognition and management. (2016, neutral): “In one study, 3 patients with metastatic renal cell carcinoma who received infusions of autologousTcells transducedwith aCARtargeting carboxyanhydrase-IX experienced grade 3-4 increases in alanine aminotransferase, aspartate aminotransferase, or total bilirubin.(20,49-51) Liver biopsies of affected ”
Engineering strategies to overcome the current roadblocks in CAR T cell therapy (2019, background): “In a clinical trial of a carbonic anhydrase IX (CAIX)-targeted CAR T cell product involving patients with renal cell carcinoma, multiple patients developed liver enzyme abnormalities 84 .”
The Principles of Engineering Immune Cells to Treat Cancer (2017, background): “…a study using a more physiologic T cell culture methodology of patients with metastatic renal cell carcinoma testing CAR T cells directed against carbonic anhydrase IX encountered severe liver toxicity, while paradoxically, there were no objective antitumor responses (Lamers et al., 2006, 2013).”