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Targeting CD20 Aggressive B-Cell Non–Hodgkin Lymphoma by Anti Published OnlineFirst December 9, 2014; DOI: 10.1158/2326-6066.CIR-14-0114 Research Article Cancer Immunology Research Targeting CD20þ Aggressive B-cell Non–Hodgkin Lymphoma by Anti-CD20 CAR mRNA-Modified Expanded Natural Killer Cells In Vitro and in NSG Mice Yaya Chu1, Jessica Hochberg1, Ashlin Yahr1, Janet Ayello1, Carmella van de Ven1, Matthew Barth2, Myron Czuczman3,4, and Mitchell S. Cairo1,5,6,7,8 Abstract þ þ þ The prognosis is very dismal for patients with relapsed CD20 also enhanced in CAR exPBNK in response to CD20 B-NHL– B-cell non-Hodgkin lymphoma (B-NHL). Facilitating the devel- specific stimulation. In Raji-Luc and Raji-2R-Luc xenografted À À opment of alternative novel therapeutic strategies is required NOD/SCID/g-chain / (NSG) mice, the luciferase signals mea- þ to improve outcomes in patients with recurrent/refractory sured in the CAR exPBNK-treated group were significantly þ CD20 B-NHL. In this study, we investigated functional activities reduced, compared with the signals measured in the untreated À of anti-CD20 CAR-modified, expanded peripheral blood NK cells mice and in mice treated with the CAR exPBNK. Furthermore, the þ (exPBNK) following mRNA nucleofection against CD20 B-NHL CAR exPBNK-treated mice had significantly extended survival þ in vitro and in vivo. CAR exPBNK had significantly enhanced in time (P < 0.001) and reduced tumor size, compared with those À þ À vitro cytotoxicity, compared with CAR exPBNK against CD20 of the untreated and the CAR exPBNK-treated mice (P < 0.05). Ramos (P < 0.05), Daudi, Raji, and two rituximab-resistant cell These preclinical data suggest that ex vivo–exPBNK modified with lines, Raji-2R and Raji-4RH (P < 0.001). As expected, there was no anti-CD20 CAR may have therapeutic potential for treating À þ significant difference against CD20 RS4;11 and Jurkat cells. patients with poor-risk CD20 hematologic malignancies. Cancer CD107a degranulation and intracellular IFNg production were Immunol Res; 3(4); 1–12. Ó2014 AACR. Introduction Study Group (UKCCSG), that children and adolescents with newly diagnosed mature B-NHL [French–American–British B-cell non-Hodgkin lymphoma (B-NHL), including Burkitt (FAB)/Lymphome malins de Burkitt (LMB) 96], have a 90% 5- lymphoma, makes up approximately 60% of all malignant NHL year overall survival (OS) following treatment with a short, that occurs in children and adolescents (1). The outcome for intensive course of chemotherapy (4). Unfortunately, for children children and adolescents with de novo mature B-NHL has and adolescents who relapse or progress with de novo mature B- improved significantly, as we previously demonstrated that short NHL, the prognosis is dismal due to chemoradiotherapy resis- but intensive chemotherapy is associated with a 90% 5-year event- tance (4, 5). Similarly, the prognosis in adults with recurrent/ free survival (EFS; refs. 2–4). We demonstrated in an international refractory Burkitt lymphoma is dismal (6). Therefore, develop- multi-cooperative group study, which comprised the Children's ment of alternative cellular targeted therapeutic strategies is Oncology Group (COG), The Societe Francaise¸ d'Oncologie required to improve outcomes in children, adolescents, and Pediatrique (SFOP), and the United Kingdom Children's Cancer adults with recurrent/refractory de novo mature B-NHL. CD20 is a glycosylated phosphoprotein expressed on the surface of B cells on all developmental stages, except pro-B cells 1 Department of Pediatrics, Maria Fareri Children's Hospital, New York or plasma cells (7). It is also expressed in >98% of childhood, Medical College, Valhalla, New York. 2Department of Pediatrics, State University of New York at Buffalo, Buffalo, New York. 3Department of adolescent, and adult mature B-cell NHLs and therefore is an Medicine, Roswell Park Cancer Institute, Buffalo, New York. 4Depart- attractive cancer therapeutic target (6, 8, 9). Rituximab, a chimeric ment of Immunology, Roswell Park Cancer Institute, Buffalo, New York. anti-CD20 antibody, has been used successfully in the treatment 5Department of Medicine, New York Medical College, Valhalla, New York. 6Department of Pathology, New York Medical College, Valhalla, of childhood and adolescent mature B-NHL as well as in New York. 7Department of Microbiology and Immunology, New York adults with diffuse large B-cell lymphoma and Burkitt lymphoma 8 Medical College, Valhalla, New York. Department of Cell Biology and (9–11). However, CD20 could also be used as a target for Anatomy, New York Medical College, Valhalla, New York. genetically engineered immune cell–based therapies. Note: Supplementary data for this article are available at Cancer Immunology Natural killer (NK) cells are bone marrow–derived cytotoxic Research Online (http://cancerimmunolres.aacrjournals.org/). lymphocytes that play a major role in the rejection of tumors and Corresponding Author: Mitchell S. Cairo, New York Medical College, 40 Sun- cells infected by viruses, even without specific immunization (12, shine Cottage Road, Skyline 1N-D12, Valhalla, NY 10595. Phone: 914-594-2150; 13). Various activating and inhibitory receptors on the NK-cell Fax: 914-594-2151; E-mail: [email protected] surface are engaged to regulate NK-cell activities and to discrim- doi: 10.1158/2326-6066.CIR-14-0114 inate target cells from healthy "self" cells (14, 15). However, Ó2014 American Association for Cancer Research. factors limiting NK therapy include small numbers of active NK www.aacrjournals.org OF1 Downloaded from cancerimmunolres.aacrjournals.org on October 3, 2021. © 2014 American Association for Cancer Research. Published OnlineFirst December 9, 2014; DOI: 10.1158/2326-6066.CIR-14-0114 Chu et al. cells in unmodified peripheral blood and a lack of specificity in University of Tennessee College of Medicine, Memphis, TN; tumor targeting (16). Our group and others have successfully ref. 17). expanded active NK cells in vitro by short-term culture with cytokines alone, using cytokines and coculture with irradiated NK-cell expansion and isolation Epstein–Barr virus (EBV)–transformed lymphoblastoid cell lines Leukocytes were obtained after informed consent from healthy as feeder cells, or using cytokines and coculture with K562 cells adult donors at the New York Blood Center. Peripheral blood expressing transfected cell-membrane bound IL15 and 4-1BBL mononuclear cells (PBMC) were obtained by Ficoll gradient (17–20). (Amersham Biosciences) separation. NK-cell expansion and iso- Chimeric antigen receptors (CAR) usually include a single- lation were performed as previously described (17) and are chain variable fragment (Fv) from a monoclonal antibody, a detailed in the Supplementary Methods. transmembrane hinge region, and a signaling domain such as CD28, CD3z, 4-1BB (CD137), or 2B4 (CD244) endodimers Production of anti-CD20-BB-z mRNA (21–24). The advantage of the CAR strategy is that no human Anti-CD20 CAR mRNA was generated as previously described leukocyte antigen (HLA) expression on the target cell is required with modifications (29). Briefly, the anti-CD20-4-1BB-CD3z was þ for the epitope to be accessible to CAR T or NK cells. Thus, it is cut from an MSCV-anti-CD20-BB-z-IRES-GFP vector and sub- not limited to only a subset of patients with a specific HLA type cloned into the pcDNA3 vector. Anti-CD20-4-1BB-CD3z mRNA þ (22). Several clinical trials testing CAR T cells in patients was transcribed in vitro using the mMESSAGE mMACHINE T7 have shown promising clinical outcomes. Porter, Grupp, Brent- Ultra Kit (Life Technologies) following the manufacturer's jens, and their colleagues (23–25) have engineered patients' instructions. The resulting product was dissolved in nuclease-free T cells with a lentiviral vector expressing anti-CD19 CAR and H2O. RNA concentrations were measured using a Nano-spectro- reinfused the anti-CD19 CAR autologous T cells into patients with photometer (Thermo Fisher) at 260 nm. refractory chronic lymphocytic leukemia and acute lymphoblastic leukemia. However, significant toxicities, including hypotension, Nucleofection fevers, renal insufficiency, cytokine-release syndrome, and B-cell Six to 8 Â 106 expanded purified NK cells were suspended in aplasia, have occurred after infusions of CAR T cells (23–26). The 100-mL nucleofection solution (Lonza); anti-CD20-BB-z mRNA hallmark toxicity of CAR T-cell therapies is cytokine-release syn- was added at 80 to 100 mg/mL. The mixture was placed in the drome, a potentially life-threatening complication of inflamma- Nucleofector Cuvette and nucleofected using the Amaxa Nucleo- tory symptoms resulting from elevated plasma cytokine levels fector II Device with U-001 program. CAR expression was detected associated with T-cell activation and proliferation (23–26). In using FITC-conjugated or AF647-conjugated goat anti-mouse IgG, 0 contrast, NK cell–based immunotherapy has not been associated F(ab )2 fragment-specific antibody (The Jackson Laboratory), and with a cytokine-release syndrome in patients; it has been associ- flow cytometry. ated with a significant NK versus leukemic effect in the absence of graft-versus-host disease (GvHD) and a significant decrease in Intracellular CD107a and IFNg assays leukemia relapse following haploidentical allogeneic stem cell Intracellular CD107a expression and IFNg were measured by transplantation in which the donor/recipient NK killer immuno- flow cytometry, as previously described (20). Intracellular CD107a globulin-like receptor (KIR)/malignant major histocompatibility and IFNg assays are detailed in the Supplementary
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