Humoral immune reconstitution after anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma

Wang, Ying; Li, Chunrui; Xia, Jieyun; Li, Ping; Cao, Jiang; Pan, Bin; Tan, Xu; Li, Hujun; Qi, Kunming; Wang, Xiangmin; Shi, Ming; Jing, Guangjun; Zhang, Yan; Cheng, Hai; Zhu, Feng; Sun, Haiying; Sang, Wei; Li, Depeng; Zhang, Xi; Li, Zhenyu; Zheng, Junnian; Liang, Aibin; Zhou, Jianfeng; Xu, Kailin

doi:10.1182/bloodadvances.2021004603

Cited by 66 publications

(79 citation statements)

References 39 publications

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“…Although, all patients who bridged to second-HSCT recovered normal immunoglobulin levels until the last follow-up. Wang et al investigated the kinetics of immunoglobin in 40 patients who received pre-HSCT CAR-T therapy and observed that the median times to IgG, IgM, and IgA recovery were 386 days, 254 days, and not reached during follow-up, respectively (27). Patients who received CAR-Ts after allo-HSCT in our study had more di culty in B-cell immune reconstitution than those who received CAR-Ts before allo-HSCT, suggesting that profound and lasting hypogammaglobulinemia cannot be resolved in patients who did not bridge to second-HSCT.…”

Section: Discussionmentioning

confidence: 99%

Long-term survival and immune reconstitution of chimeric antigen receptor T-cell therapy for childhood molecular relapse of B-cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation

Zhang

Hu²,

yingxi³

et al. 2022

Preprint

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Measurable residual disease (MRD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an independent risk factor for relapse in patients with acute lymphoblastic leukemia (ALL). This study aimed to assess the efficacy, safety, and immune reconstitution of chimeric antigen receptor T-cell (CAR-T) therapy in patients with molecular relapse after allo-HSCT. Eleven patients with molecular relapse of B-cell-ALL who underwent CAR-T therapy after allo-HSCT were enrolled. The rate of MRD negativity after a month of CAR-T infusion was 81.8%. Patients who bridged to second-HSCT after CAR-T therapy (n = 3) showed a trend of higher 3-year leukemia-free survival and 3-year overall survival than those who did not (n = 8; 100% vs. 75.0%; 95% CI, 45.0–104.9%; P = 0.370). No treatment-related mortalities were observed. Among patients who did not bridge to second-HSCT and remained in complete remission until the last follow-up (n = 6), five of them had not recovered normal immunoglobulin concentrations with a median follow-up of 43 months. CAR-T therapy may be a safe and effective treatment strategy to improve survival after allo-HSCT; however, the problem of prolonged hypogammaglobulinemia in patients who do not bridge to second-HSCT is worth noting.

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Section: Discussionmentioning

confidence: 99%

Long-term survival and immune reconstitution of chimeric antigen receptor T-cell therapy for childhood molecular relapse of B-cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation

Zhang

Hu²,

yingxi³

et al. 2022

Preprint

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“…Although patients receive intravenous immunoglobulin replacement to compensate for loss of normal B-cell or plasma cell function, some are prone to infection and exhibit long-term defects in humoral immunity. 35,36 In addition, neurotoxicity as an adverse effect of anti-CD19 therapy suggests "on-target, off-tumor" adverse effects likely due to CD19 expression on brain mural cells. 37 Antigen selection in solid tumors is more challenging than in hematological cancers because the "on-target, off-tumor" effects of solid tumor antigens often have more severe consequences in normal tissue function compared with B-cell aplasia (Fig.…”

Section: T Cell-intrinsic Limitationsmentioning

confidence: 99%

Chimeric Antigen Receptor T-Cell Therapy

Brookens

Posey

2023

Cancer J

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Genetically engineered chimeric antigen receptor (CAR) T-cell therapy leverages the ability of the immune system to eliminate tumors and redirects cytotoxic functions toward cells expressing specified tumor-restricted antigens. Although 6 CAR T-cell therapies have received Food and Drug Administration (FDA) approval for the treatment of many hematological malignancies, limitations involving T cell-intrinsic, T cell-extrinsic, and therapeutic factors remain in the treatment of both liquid and solid tumors. Chimeric antigen receptor design, signals from the tumor microenvironment, tumor antigen escape mechanisms, and systemic inflammatory consequences of CAR T-cell infusion all influence the efficacy and feasibility of CAR T-cell therapy in different malignancies. Here, we review the core structure of the CAR, the evolution of different CAR generations, CAR T-cell therapy limitations, and current strategies being investigated to overcome the T cell-intrinsic, T cell-independent, and therapeutic barriers to successful CAR T-cell therapy.

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“…[39][40][41] One study showed that anti-BCMA CAR T cells caused a 7-month aplasia of normal BM plasma cells and a longer period of hypogammaglobulinemia. 42 Thus, protecting this patient population from infections is essential.…”

Section: Open Accessmentioning

confidence: 99%

Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma

Sui

et al. 2022

J Immunother Cancer

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BackgroundAnti-B-cell maturation antigen (BCMA) chimeric antigen receptor T-cell (CAR T) therapy showed remarkable efficacy in patients with relapsed or refractory multiple myeloma (RRMM). This phase 1 dose-escalation and expansion study developed C-CAR088, a novel second-generation humanized anti-BCMA CAR T-cell therapy, and assessed the safety and efficacy of three dosages of C-CAR088 in patients with RRMM.MethodsPatients received lymphodepletion with three doses of cyclophosphamide (300 mg/m2) and three doses of fludarabine (30 mg/m2) on days –5, –4, and –3, followed by an infusion of C-CAR088 on day 0. Doses of 1.0×106, 3.0×106, and 6.0×106 CAR T cells/kg (±20%) were tested in the dose-escalation cohorts and expansion cohorts. The primary endpoint was treatment safety, including the rate of treatment-emergent adverse events after cell infusion. Secondary endpoints were the overall response rate and progression-free survival. The exploratory endpoints were the quantification of C-CAR088 CAR T cells, selection of cytokines and chemokines in blood, and measurement of tumor BCMA expression.ResultsAs of July 2, 2021, 31 patients had been infused with C-CAR088. Any grade cytokine release syndrome (CRS) occurred in 29 patients (93.5%), and grade 3 CRS occurred in 3 patients (9.7%). One patient from the high-dose group (4.5–6.0×106 CAR T cells/kg) developed grade 1 neurotoxicity. No dose-limiting toxicities were observed in any dose group, and all adverse events were reversible after proper management. The overall response, stringent complete response, complete response (CR), and very good partial response rates were 96.4%, 46.4%, 10.7%, and 32.1%, respectively. The CR rate in the medium-dose (3.0×106 CAR T cells/kg) and high-dose (4.5–6.0×106 CAR T cells/kg) groups was 54.5% and 71.4%, respectively. In the CR group, 15 (93.7%) patients achieved minimal residual disease (MRD) negativity (test sensitivity >1/10−5). All seven patients with double-hit or triple-hit multiple myeloma achieved MRD-negative CR.ConclusionsThe present study demonstrated that C-CAR088 had a good safety profile and high antitumor activity in patients with RRMM, constituting a promising treatment option for RRMM.Trial registration numberNCT03815383, NCT03751293, NCT04295018, and NCT04322292.

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Humoral immune reconstitution after anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma

Cited by 66 publications

References 39 publications

Long-term survival and immune reconstitution of chimeric antigen receptor T-cell therapy for childhood molecular relapse of B-cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation

Long-term survival and immune reconstitution of chimeric antigen receptor T-cell therapy for childhood molecular relapse of B-cell acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation

Chimeric Antigen Receptor T-Cell Therapy

Phase 1 study of C-CAR088, a novel humanized anti-BCMA CAR T-cell therapy in relapsed/refractory multiple myeloma

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