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Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus.

ABSTRACT: The failure of anti-CD20 antibody (Rituximab) as therapy for lupus may be attributed to the transient and incomplete B cell depletion achieved in clinical trials. Here, using an alternative approach, we report that complete and sustained CD19⁺ B cell depletion is a highly effective therapy in lupus models. CD8⁺ T cells expressing CD19-targeted chimeric antigen receptors (CARs) persistently depleted CD19⁺ B cells, eliminated autoantibody production, reversed disease manifestations in target organs, and extended life spans well beyond normal in the (NZB × NZW) F₁ and MRL ^fas/fas mouse models of lupus. CAR T cells were active for 1 year in vivo and were enriched in the CD44⁺CD62L⁺ T cell subset. Adoptively transferred splenic T cells from CAR T cell-treated mice depleted CD19⁺ B cells and reduced disease in naive autoimmune mice, indicating that disease control was cell-mediated. Sustained B cell depletion with CD19-targeted CAR T cell immunotherapy is a stable and effective strategy to treat murine lupus, and its effectiveness should be explored in clinical trials for lupus.

SUBMITTER: Kansal R

PROVIDER: S-EPMC8201923 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus.

Kansal Rita R Richardson Noah N Neeli Indira I Khawaja Saleem S Chamberlain Damian D Ghani Marium M Ghani Qurat-Ul-Ain QU Balazs Louisa L Beranova-Giorgianni Sarka S Giorgianni Francesco F Kochenderfer James N JN Marion Tony T Albritton Lorraine M LM Radic Marko M

Science translational medicine 20190301 482

The failure of anti-CD20 antibody (Rituximab) as therapy for lupus may be attributed to the transient and incomplete B cell depletion achieved in clinical trials. Here, using an alternative approach, we report that complete and sustained CD19+ B cell depletion is a highly effective therapy in lupus models. CD8+ T cells expressing CD19-targeted chimeric antigen receptors (CARs) persistently depleted CD19+ B cells, eliminated autoantibody production, reversed disea ...[more]

PMID: 30842314

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Project description:BackgroundFor CD19-positive relapsed/refractory B-cell acute lymphoblastic leukemia (r/r B-ALL) after treatment with murine CD19 (mCD19) CAR-T, the reinfusion of mCD19 CAR-T cells may be ineffective due to anti-mouse single-chain variable fragment (scFv) antibody caused by mCD19 CAR. To overcome this immunogenicity, we applied humanized CD19 (hCD19) CAR-T cells to treat r/r B-ALL patients with prior mCD19 CAR-T therapy.MethodsNineteen pediatric and adult patients were included, 16 relapsed after and 3 were primarily resistant to mCD19 CAR-T. All patients presented with more than 5% blasts in bone marrow and/or extramedullary disease, and still showed CD19 antigen expression. Humanized CD19-CARs were lentiviral vectors carrying a second generation CAR with 4-1-BB co-stimulatory and CD3ζ signaling domains. Patient-derived cells were collected for producing CAR-T cells, the median dose of infused hCD19 CAR-T cells was 2.4 × 105/kg (range, 1.0-18.0 × 105/kg).ResultshCD19 CAR-T resulted in a complete remission (CR) rate of 68% (13/19). Among 13 remission patients, 11 underwent allogeneic hematopoietic cell transplantation (allo-HCT) (3 were second HCT) and 10 remained in CR; the event-free survival rates at 12-18 months were 91% in 11 patients received following allo-HCT and 69% in all CR patients. Six cases had no response to hCD19 CAR-T, 3 died of disease progression; another 3 received salvage second transplantation, of them, 2 relapsed again (one died). Cytokine release syndrome (CRS) occurred in 95% (18/19) of patients, most CRS events were grade 1 and grade 2 (n = 17), there was only one grade 4 CRS. Two cases experienced grade 1 neurotoxicity.ConclusionsHumanized CD19 CAR-T cell therapy could be a treatment option for CD19-positive B-ALL patients who relapsed after or resisted prior murine CD19 CAR-T, hCD19 CAR-T followed by allo-HCT provided a longer remission in CR patients. Nevertheless, the prognosis of non-responders to hCD19 CAR-T remained dismal.Trial registrationChinese Clinical Trial Registry/WHO International Clinical Trial Registry ( ChiCTR1900024456 , URL: www.chictr.org.cn ); registered on July 12, 2019.

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Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus.

Publications

Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus.

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