title: CD19 target-engineered T-cells accumulate at tumor lesions in human B-cell lymphoma xenograft mouse models.
abstract: Adoptive T-cell therapy with CD19-specific chimeric antigen receptors (CARs) is promising for treatment of advanced B-cell malignancies. Tumor targeting of CAR-modified T-cells is likely to contribute therapeutic potency; therefore we examined the relationship between the ability of CD19-specific CAR (CD19-CAR)-transduced T-cells to accumulate at CD19(+) tumor lesions, and their ability to provide anti-tumor effects in xenograft mouse models. Normal human peripheral blood lymphocytes, activated with immobilized RetroNectin and anti-CD3 antibodies, were transduced with retroviral vectors that encode CD19-CAR. Expanded CD19-CAR T-cells with a high transgene expression level of about 75% produced IL-2 and IFN-γ in response to CD19, and lysed both Raji and Daudi CD19(+) human B-cell lymphoma cell lines. Furthermore, these cells efficiently accumulated at Raji tumor lesions where they suppressed tumor progression and prolonged survival in tumor-bearing Rag2(-/-)γc(-/-) immunodeficient mice compared to control cohorts. These results show that the ability of CD19-CAR T-cells to home in on tumor lesions is pivotal for their anti-tumor effects in our xenograft models, and therefore may enhance the efficacy of adoptive T-cell therapy for refractory B-cell lymphoma.
authors.affiliation: Division of Genetic Therapeutics, Center for Molecular Medicine, Jichi Medical University, Japan. ttsukahara@jichi.ac.jp
authors.forename: Tomonori
authors.initials: T
authors.lastname: Tsukahara
authors.forename: Ken
authors.initials: K
authors.lastname: Ohmine
authors.forename: Chihiro
authors.initials: C
authors.lastname: Yamamoto
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Uchibori
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ido
authors.forename: Takeshi
authors.initials: T
authors.lastname: Teruya
authors.forename: Masashi
authors.initials: M
authors.lastname: Urabe
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Mizukami
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kume
authors.forename: Masataka
authors.initials: M
authors.lastname: Nakamura
authors.forename: Junichi
authors.initials: J
authors.lastname: Mineno
authors.forename: Kazutoh
authors.initials: K
authors.lastname: Takesako
authors.forename: Isabelle
authors.initials: I
authors.lastname: Riviere
authors.forename: Michel
authors.initials: M
authors.lastname: Sadelain
authors.forename: Renier
authors.initials: R
authors.lastname: Brentjens
authors.forename: Keiya
authors.initials: K
authors.lastname: Ozawa
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D018941:Antigens, CD19 / Q000235:genetics / Q000276:immunology*; D045744:Cell Line, Tumor; D006801:Humans; D016393:Lymphoma, B-Cell / Q000276:immunology* / Q000473:pathology*; D051379:Mice; D008807:Mice, Inbred BALB C; D015202:Protein Engineering / Q000379:methods; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology*
chemical_list: D018941:Antigens, CD19
keywords: Adoptive T-cell therapy; B-cell lymphoma; CAR; CD19; CD19-CAR T-cells; CD19-specific CAR-transduced T-cells; Chimeric antigen receptor; Tumor targeting; chimeric antigen receptor