Preserved Activity of CD20-Specific Chimeric Antigen Receptor-Expressing T Cells in the Presence of Rituximab

Cancer Immunol Res. 2016 Jun;4(6):509-19. doi: 10.1158/2326-6066.CIR-15-0276. Epub 2016 Apr 21.

Abstract

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°C blockade was incomplete at concentrations up to 200 μg/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 μg/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 μg/mL (interquartile range, 19-72 μg/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. Cancer Immunol Res; 4(6); 509-19. ©2016 AACR

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Antigens, CD20 / drug effects
  • Antigens, CD20 / immunology*
  • Antigens, CD20 / metabolism
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Cell Proliferation / drug effects
  • Combined Modality Therapy
  • Cytokines / biosynthesis
  • Cytotoxicity, Immunologic / drug effects
  • Dose-Response Relationship, Drug
  • Humans
  • Immunotherapy, Adoptive / methods
  • Lymphoma, B-Cell / immunology
  • Lymphoma, B-Cell / therapy*
  • Mice, Inbred NOD
  • Mice, SCID
  • Receptors, Antigen, T-Cell / metabolism*
  • Rituximab / administration & dosage
  • Rituximab / pharmacology*
  • T-Lymphocyte Subsets / drug effects*
  • T-Lymphocyte Subsets / immunology
  • T-Lymphocyte Subsets / transplantation
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antigens, CD20
  • Antineoplastic Agents
  • Cytokines
  • Receptors, Antigen, T-Cell
  • Rituximab