Patrolling monocytes scavenge endothelial-adherent sickle RBCs: a novel mechanism of inhibition of vaso-occlusion in SCD

Liu, Yunfeng; Zhong, Hui; Bao, Weili; Mendelson, Avital; An, Xiuli; Shi, Patricia A.; Chou, Stella T.; Manwani, Deepa; Yazdanbakhsh, Karina

doi:10.1182/blood.2019000172

Cited by 31 publications

(30 citation statements)

References 77 publications

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“…1–2 (59%), gr. ≥ 3 (41%) sCR/CR (82%)/VGPR (6%) NCT03090659 (2) [ 49 , 50 ] (LCAR-B38M) 57 Llama V H H aCD3/CD28 + IL-2 Lentiviral 4-1BB 0.07–2,1 × 10 6 /kg CP CRS gr. 1–2 (82%), gr.…”

Section: Resultsmentioning

confidence: 99%

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma

et al. 2020

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Background B-cell maturation antigen (BCMA)-targeted chimeric antigen receptor (CAR)-T-cell therapy is an emerging treatment option for multiple myeloma. The aim of this systematic review and meta-analysis was to determine its safety and clinical activity and to identify factors influencing these outcomes. Methods We performed a database search using the terms “BCMA,” “CAR,” and “multiple myeloma” for clinical studies published between 01/01/2015 and 01/01/2020. The methodology is further detailed in PROSPERO (CRD42020125332). Results Twenty-three different CAR-T-cell products have been used so far in 640 patients. Cytokine release syndrome was observed in 80.3% (69.0–88.2); 10.5% (6.8–16.0) had neurotoxicity. A higher neurotoxicity rate was reported in studies that included more heavily pretreated patients: 19.1% (13.3–26.7; I2 = 45%) versus 2.8% (1.3–6.1; I2 = 0%) (p < 0.0001). The pooled overall response rate was 80.5% (73.5–85.9); complete responses (CR) were observed in 44.8% (35.3–54.6). A pooled CR rate of 71.9% (62.8–79.6; I2 = 0%) was noted in studies using alpaca/llama-based constructs, whereas it was only 18.0% (6.5–41.1; I2 = 67%) in studies that used retroviral vectors for CAR transduction. Median progression-free survival (PFS) was 12.2 (11.4–17.4) months, which compared favorably to the expected PFS of 1.9 (1.5–3.7) months (HR 0.14; p < 0.0001). Conclusions Although considerable toxicity was observed, BCMA-targeted CAR-T-cell therapy is highly efficacious even in advanced multiple myeloma. Subgroup analysis confirmed the anticipated inter-study heterogeneity and identified potential factors contributing to safety and efficacy. The results of this meta-analysis may assist the future design of CAR-T-cell studies and lead to optimized BCMA CAR-T-cell products.

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Section: Resultsmentioning

confidence: 99%

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma

et al. 2020

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“…In the present cohort, we did not find any difference in the monocyte subtype ratio between the patients and the controls ( Figure 5A ), suggesting no role for subset-specific monocytes in iDC differentiation and no correlation of a monocyte subset with DCs compartment changes. Monocytes from patients with SCD are constantly exposed to heme released during hemolysis, and there is evidence that they can upregulate HO-1, which metabolizes heme into CO (carbon monoxide), Fe (iron), and biliverdin ( 33 , 34 ). Thus, we evaluated HO-1 expression by monocytes, and found that monocytes from the patients overall demonstrated upregulation of HO-1 compared to that from the controls.…”

Section: Resultsmentioning

confidence: 99%

Inflammatory Dendritic Cells Contribute to Regulate the Immune Response in Sickle Cell Disease

et al. 2021

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Sickle cell disease (SCD), one of the most common hemoglobinopathies worldwide, is characterized by a chronic inflammatory component, with systemic release of inflammatory cytokines, due to hemolysis and vaso-occlusive processes. Patients with SCD demonstrate dysfunctional T and B lymphocyte responses, and they are more susceptible to infection. Although dendritic cells (DCs) are the main component responsible for activating and polarizing lymphocytic function, and are able to produce pro-inflammatory cytokines found in the serum of patients with SCD, minimal studies have thus far been devoted to these cells. In the present study, we identified the subpopulations of circulating DCs in patients with SCD, and found that the bloodstream of the patients showed higher numbers and percentages of DCs than that of healthy individuals. Among all the main DCs subsets, inflammatory DCs (CD14+ DCs) were responsible for this rise and correlated with higher reticulocyte count. The patients had more activated monocyte-derived DCs (mo-DCs), which produced MCP-1, IL-6, and IL-8 in culture. We found that a CD14+ mo-DC subset present in culture from some of the patients was the more activated subset and was mainly responsible for cytokine production, and this subset was also responsible for IL-17 production in co-culture with T lymphocytes. Finally, we suggest an involvement of heme oxygenase in the upregulation of CD14 in mo-DCs from the patients, indicating a potential mechanism for inducing inflammatory DC differentiation from circulating monocytes in the patients, which correlated with inflammatory cytokine production, T lymphocyte response skewing, and reticulocyte count.

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“…Nanobodies have demonstrated their potential and feasibility in the discovery and development of CAR-T therapies. PRG1801 is composed of a monovalent anti-BCMA nanobody, 4-1BB, and CD3ζ [ 77 , 108 ], while the other anti-BCMA CAR-T developed by Nanjing Legend Biotech employed two nanobodies recognizing BCMA in a bi-epitopic manner [ 75 , 76 , 109 , 110 ]. Based on the published data, their clinical effects are both comparable to that of bb2121, which was developed by Bluebird with the use of an scFv targeted BCMA [ 100 ].…”

Section: The Clinical Effects Of Different Anti-bcma Car-t Cellsmentioning

confidence: 99%

The Application of Nanobody in CAR-T Therapy

Bao

Gao

et al. 2021

Biomolecules

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Chimeric antigen receptor (CAR) T therapy represents a form of immune cellular therapy with clinical efficacy and a specific target. A typical chimeric antigen receptor (CAR) construct consists of an antigen binding domain, a transmembrane domain, and a cytoplasmic domain. Nanobodies have been widely applied as the antigen binding domain of CAR-T due to their small size, optimal stability, high affinity, and manufacturing feasibility. The nanobody-based CAR structure has shown a proven function in more than ten different tumor-specific targets. After being transduced in Jurkat cells, natural killer cells, or primary T cells, the resulting nanobody-based CAR-T or CAR-NK cells demonstrate anti-tumor effects both in vitro and in vivo. Interestingly, anti-BCMA CAR-T modulated by a single nanobody or bi-valent nanobody displays comparable clinical effects with that of single-chain variable fragment (scFv)-modulated CAR-T. The application of nanobodies in CAR-T therapy has been well demonstrated from bench to bedside and displays great potential in forming advanced CAR-T for more challenging tasks.

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Patrolling monocytes scavenge endothelial-adherent sickle RBCs: a novel mechanism of inhibition of vaso-occlusion in SCD

Cited by 31 publications

References 77 publications

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma

Safety and clinical efficacy of BCMA CAR-T-cell therapy in multiple myeloma

Inflammatory Dendritic Cells Contribute to Regulate the Immune Response in Sickle Cell Disease

The Application of Nanobody in CAR-T Therapy

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