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Clinical Trial
. 2013 Apr;21(4):904-12.
doi: 10.1038/mt.2013.17. Epub 2013 Feb 19.

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

Cor Hj Lamers  1 , Stefan Sleijfer, Sabine van Steenbergen, Pascal van Elzakker, Brigitte van Krimpen, Corrien Groot, Arnold Vulto, Michael den Bakker, Egbert Oosterwijk, Reno Debets, Jan W Gratama
Affiliations
Clinical Trial

V体育安卓版 - Treatment of metastatic renal cell carcinoma with CAIX CAR-engineered T cells: clinical evaluation and management of on-target toxicity

Cor Hj Lamers et al. Mol Ther. 2013 Apr.

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) VSports手机版. 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. .

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Figures

Figure 1
Figure 1
Consort diagram showing compliance to eligibility criteria and protocol treatment. CAIX, carboxy-anhydrase-IX; CAR, chimeric antibody receptor; mAb, monoclonal antibody; MTD, maximum tolerated dose.
Figure 2
Figure 2
T cell infiltration in liver. Immunohistochemistry of biopsy of liver taken from patient 8 at day 4, i.e., 2 days after last CAR T cell infusion (original magnification ×200, all sections), showing liver parenchyma (L), portal triangle (P) with bile duct (B) and stained for expression of CAIX antigen and for CD3, CD4, and CD8 T cells. CD8 T cells were lining at the basal side (arrowheads) or infiltrating (arrow) the epithelium of the bile duct. CAIX, carboxy-anhydrase-IX; CAR, chimeric antibody receptor.
Figure 3
Figure 3
CAR-specific IFN-γ production by post-treatment PBMC correlates with pre-infusion CAR T cell IFN-γ production potency. Maximum IFN-γ production by CAR T cells in 1 × 106 PBMC per 24 hours is calculated from the IFN-γ production of pre-infusion CAR T cells and the proportion of CAR T cells in PBMC and is expressed as pg IFN-γ/106 PBMC/24 hours, see Supplementary Table S3b. The measured IFN-γ production in post-treatment PBMC correlates with the calculated maximum IFN-γ production by CAR T cells in PBMC; this correlation is significant (Pearson's correlation analysis: r = 0.452; P = 0.04; regression line: y = 23 + 0.32x). CAR, chimeric antibody receptor; IFN, interferon; PBMC, peripheral blood mononuclear cell.
Figure 4
Figure 4
Blood cytokine levels. Blood cytokine levels were assessed in plasma samples obtained before, during, and following CAIX CAR T cell therapy by cytokine bead arrays. For both treatment cycles, pre-treatment (day 1) and peak levels are shown for individual patients. Peak day is presented as median and range. CAIX, carboxy-anhydrase-IX; CAR, chimeric antibody receptor; IFN, interferon; IL, interleukin; TNF, tumor necrosis factor.
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