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posted on 2023-03-31, 18:16 authored by Marco Ruella, Saad S. Kenderian, Olga Shestova, Joseph A. Fraietta, Sohail Qayyum, Qian Zhang, Marcela V. Maus, Xiaobin Liu, Selene Nunez-Cruz, Michael Klichinsky, Omkar U. Kawalekar, Michael Milone, Simon F. Lacey, Anthony Mato, Stephen J. Schuster, Michael Kalos, Carl H. June, Saar Gill, Mariusz A. Wasik Supplementary Methods: Fluorescence in situ hybridization (FISH); MTT (3-(4,5-dimethylthiazolyl-2)-2,5-diphenyltetrazolium bromide) enzymatic conversion assay; Western blot analysis; Multiparametric flow cytometry; Table S1. List of the antibodies used for multiparametric flow cytometry; Degranulation assay; Proliferation assay; Cytotoxicity assays; Cytokine measurements; Animal experiments; Figure S1. Different sensitivity to ibrutinib in hematological cell lines; Figure S2. MCL-RL engrafted mice: tumor burden and histology; Figure S3. CTL019 design and production; Figure S4. CTL019 cell production from primary MCL samples; Figure S5. Effect of ibrutinib in T cell function in vitro and in vivo; Figure S5. Effect of ibrutinib in T cell function in vitro and in vivo. A. CTL019 proliferation assay in the presence of ibrutinib;Figure S6. Peripheral blood T cell subsets in mice treated with CART19 or CART19-ibrutinib; Figure S7. CXCR4 and inhibitory/costimulatory receptor expression in peripheral blood of mice treated with CART19 or CART19-ibrutinib; Figure S8. A. Ibrutinib did not enhance the anti-tumor activity of control untransduced T cells.
Funding
University of Pennsylvania-Novartis Research Alliance, Lymphoma Research Foundation
American Society of Hematology
NCI
NIH
Jim and Frannie Maguire Lymphoma Research Fund
History
ARTICLE ABSTRACT
Purpose: Responses to therapy with chimeric antigen receptor T cells recognizing CD19 (CART19, CTL019) may vary by histology. Mantle cell lymphoma (MCL) represents a B-cell malignancy that remains incurable despite novel therapies such as the BTK inhibitor ibrutinib, and where data from CTL019 therapy are scant. Using MCL as a model, we sought to build upon the outcomes from CTL019 and from ibrutinib therapy by combining these in a rational manner.Experimental Design: MCL cell lines and primary MCL samples were combined with autologous or normal donor-derived anti-CD19 CAR T cells along with ibrutinib. The effect of the combination was studied in vitro and in mouse xenograft models.Results: MCL cells strongly activated multiple CTL019 effector functions, and MCL killing by CTL019 was further enhanced in the presence of ibrutinib. In a xenograft MCL model, we showed superior disease control in the CTL019- as compared with ibrutinib-treated mice (median survival not reached vs. 95 days, P < 0.005) but most mice receiving CTL019 monotherapy eventually relapsed. Therefore, we added ibrutinib to CTL019 and showed that 80% to 100% of mice in the CTL019 + ibrutinib arm and 0% to 20% of mice in the CTL019 arm, respectively, remained in long-term remission (P < 0.05).Conclusions: Combining CTL019 with ibrutinib represents a rational way to incorporate two of the most recent therapies in MCL. Our findings pave the way to a two-pronged therapeutic strategy in patients with MCL and other types of B-cell lymphoma. Clin Cancer Res; 22(11); 2684–96. ©2016 AACR.
