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The use of chimeric antigen receptor T cells in patients with non-Hodgkin lymphoma.

ABSTRACT: Resistance to conventional lines of therapy develops in approximately 20% of all patients with lymphoma. These patients have a dismal prognosis, with an expected median survival of 6.3 months. In recent years, T-cell immunotherapy has demonstrated a remarkable capacity to induce complete and durable clinical responses in patients with chemotherapy-refractory lymphoma. A major contributor to the success of immunotherapy has been the advent of genetic engineering technologies that introduce a chimeric antigen receptor (CAR) into T cells to focus their killing activity on tumor cells. The adoptive transfer of autologous CAR T-cell products specific for the pan-B-cell antigen CD19 have now received approval from the US Food and Drug Administration (FDA) for the treatment of relapsed or chemotherapy-resistant B-cell non-Hodgkin lymphoma. This review is designed to showcase the clinical efficacy and unique toxicities of individually developed CAR T-cell products for the treatment of lymphomas and their evolution from the laboratory bench to commercialization.

SUBMITTER: Lulla PD

PROVIDER: S-EPMC6469642 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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The use of chimeric antigen receptor T cells in patients with non-Hodgkin lymphoma.

Lulla Premal D PD Hill LaQuisa C LC Ramos Carlos A CA Heslop Helen E HE

Clinical advances in hematology & oncology : H&O 20180501 5

Resistance to conventional lines of therapy develops in approximately 20% of all patients with lymphoma. These patients have a dismal prognosis, with an expected median survival of 6.3 months. In recent years, T-cell immunotherapy has demonstrated a remarkable capacity to induce complete and durable clinical responses in patients with chemotherapy-refractory lymphoma. A major contributor to the success of immunotherapy has been the advent of genetic engineering technologies that introduce a chim ...[more]

PMID: 29851933

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Project description:NK-92 a continuously growing cell line bioengineered to express human anti-CD19 chimeric antigen receptor (CAR) CD19.TaNK recognizing CD19+ B cells represents as potential “off the shelf” therapy candidate for B cell malignancies. The goal of this study was to establish the mechanistic rationale for CD19.TaNK therapy in B-cell NHL (bNHL) and to determine the therapeutic potency in vitro against a host of bNHL cell lines, patient derived primary cell lines (including anti-CD20 antibody resistant cell lines), and in in vivo mouse models. We utilized bNHL cell lines SU-DHL10, SU-DHL4, SU-DHL2 (DLBCL), HF-1 (follicular) and Raji (Burkitt’s) and Rituximab- (RR) and obinutuzumab (OR)-resistant bNHL cell lines (SU-DHL2, SU-DHL4, SU-DHL10), and patient derived primary cells (EL-5 and KSC) were investigated the cytolytic activity of CD19.TaNK. We observed significantly increased CD19.TaNK mediated cytolytic activity at E:T ratios (1:1-10:1) via LDH release in all bNHL cell lines and CD20 resistant bHNL cells. Further, the dynamic efficacy of CD19.TaNK determined using droplet based single cell microfluidics analysis of cell interactions (1:1) between CD19.TaNK and anti-CD20 sensitive or resistant bNHL cell showed that vast majority of the cells were killed by single contact >80% (SU-DHL 4, SUD-HL 4 -OR), 40% (SU-DHL10-RR), >60% (SU-DHL10, SUD-HL-10-OR) and 40% (SU-DHL10-RR) within first 40 minutes, while the remainder were killed through events requiring multiple contacts. Thus, suggesting that CD19.TaNK indiscriminately kills both anti-CD20 sensitive and resistant cells. Global transcriptome analysis performed using flow sorted bNHL co-cultured with CD19.TaNK at 1:1 ratio for two hours, revealed conserved activation of IFNγ signaling, execution of apoptosis, ligand binding, immunoregulatory or chemokine signaling pathways in these bNHL cells. Using proximity extension assay based 92-plex cytokine panel we observed increased secretion of various cytokines, granzymes and decreased secretions of ADA, HO-1, CD5, CD28, CD70, CD244, IFN and TNF consistently with anti-CD20 sensitive and resistant cells. Altogether these results demonstrate that CD19.TaNK inflicts mechanistically conserved killing activity against different bNHL cell lines, including in anti-CD20 refractory bNHL. Finally, in SCID mice experiments we observed marked reduction in the volume of SU-DHL10 derived tumor xenografts with infusion of CD19.TaNK compared to control. Overall, we observed potent anti-lymphoma activity with CD19.TaNK involving biologically conserved mechanisms indicating that CD19.TaNK could be equally active under untreated or refractory bNHL in the clinical settings.

Dataset Information

The use of chimeric antigen receptor T cells in patients with non-Hodgkin lymphoma.

Publications

The use of chimeric antigen receptor T cells in patients with non-Hodgkin lymphoma.

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