Journal
CANCER IMMUNOLOGY RESEARCH
Volume 4, Issue 6, Pages 509-519Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/2326-6066.CIR-15-0276
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Funding
- NCI NIH HHS [R01 CA136551, P01 CA044991, P30 CA015704, K08 CA151682, K24 CA184039, K23 CA154874, T32 CA009515] Funding Source: Medline
- NIDDK NIH HHS [P30 DK056465, U54 DK106829] Funding Source: Medline
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CD20 is an attractive immunotherapy target for B-cell non-Hodgkin lymphomas, and adoptive transfer of T cells genetically modified to express a chimeric antigen receptor (CAR) targeting CD20 is a promising strategy. A theoretical limitation is that residual serum rituximab might block CAR binding to CD20 and thereby impede T cell-mediated anti-lymphoma responses. The activity of CD20 CAR-modified T cells in the presence of various concentrations of rituximab was tested in vitro and in vivo. CAR-binding sites on CD20(+) tumor cells were blocked by rituximab in a dose-dependent fashion, although at 37 degrees C blockade was incomplete at concentrations up to 200 mu g/mL. T cells with CD20 CARs also exhibited modest dose-dependent reductions in cytokine secretion and cytotoxicity, but not proliferation, against lymphoma cell lines. At rituximab concentrations of 100 mg/mL, CAR T cells retained >= 50% of baseline activity against targets with high CD20 expression, but were more strongly inhibited when target cells expressed low CD20. In a murine xenograft model using a rituximab-refractory lymphoma cell line, rituximab did not impair CAR T-cell activity, and tumors were eradicated in >85% of mice. Clinical residual rituximab serum concentrations were measured in 103 lymphoma patients after rituximab therapy, with the median level found to be only 38 mg/mL (interquartile range, 19-72 mu g/mL). Thus, despite modest functional impairment in vitro, the in vivo activity of CD20-targeted CAR T cells remains intact at clinically relevant levels of rituximab, making use of these T cells clinically feasible. (C) 2016 AACR.
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