title: Preserved Activity of CD20-Specific Chimeric Antigen Receptor-Expressing T Cells in the Presence of Rituximab.
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
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Rufener
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Oliver W
authors.initials: OW
authors.lastname: Press
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Philip
authors.initials: P
authors.lastname: Olsen
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Sang Yun
authors.initials: SY
authors.lastname: Lee
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Seattle Children's Research Institute, Seattle, Washington.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Jensen
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Ajay K
authors.initials: AK
authors.lastname: Gopal
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Barbara
authors.initials: B
authors.lastname: Pender
authors.affiliation: City of Hope Medical Center, Duarte, California.
authors.forename: Lihua E
authors.initials: LE
authors.lastname: Budde
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington.
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Rossow
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Damian J
authors.initials: DJ
authors.lastname: Green
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: David G
authors.initials: DG
authors.lastname: Maloney
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington.
authors.forename: Stanley R
authors.initials: SR
authors.lastname: Riddell
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington. Division of Medical Oncology, University of Washington School of Medicine, Seattle, Washington. tillb@fhcrc.org.
authors.forename: Brian G
authors.initials: BG
authors.lastname: Till
mesh_terms: D000818:Animals; D018951:Antigens, CD20 / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D049109:Cell Proliferation / Q000187:drug effects; D003131:Combined Modality Therapy; D016207:Cytokines / Q000096:biosynthesis; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods; D016393:Lymphoma, B-Cell / Q000276:immunology / Q000628:therapy*; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D000069283:Rituximab / Q000008:administration & dosage / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000637:transplantation; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D018951:Antigens, CD20; D000970:Antineoplastic Agents; D016207:Cytokines; D011948:Receptors, Antigen, T-Cell; D000069283:Rituximab