The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma

Wei, Jianshu; Liu, Yang; Wang, Chunmeng; Zhang, Yajing; Tong, Chuan; Dai, Guanghai; Wang, Wei; Rasko, John E.J.; Melenhorst, J. Joseph; Han, Weidong; Liang, Aibin; Han, Weidong

doi:10.1038/s41392-020-00256-x

Cited by 98 publications

(111 citation statements)

References 106 publications

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“…After co-culturing with αvβ6-positive cells, A20-2G CAR T cells produced greater levels of IFN-γ than A20-4G CAR T cells (4.5±1.9% vs. 1.1±0.7%; p =0.0156) ( Figures 6A,B ). This may be an advantage of A20-4G CAR T cells since clinical studies of the 4G CAR T cells targeting CD19 found that low levels of IFN-γ might be beneficial to limit CAR T cell-mediated cytokine release syndrome (CRS) ( 10 , 15 ), which was often observed in patients who received CAR T cell therapy ( 48 , 49 ). Furthermore, A20-4G CAR T cells showed a higher proliferation rate than A20-2G CAR T cells (74.6±5.9% vs. 56.5±5.5%, p =0.0175) ( Figures 6C,D ).…”

Section: Discussionmentioning

confidence: 99%

Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells

et al. 2021

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Cholangiocarcinoma (CCA) is a lethal bile duct cancer that responds poorly to current standard treatments. A new therapeutic approach is, therefore, urgently needed. Adoptive T cell transfer using chimeric antigen receptor (CAR) T cells is a new therapeutic modality with demonstrated efficacy in hematologic malignancies. However, its efficacy against solid tumors is modest, and further intensive investigation continues. An important factor that influences the success of CAR T cell therapy is the selection of a target antigen that is highly expressed on cancer cells, but markedly less so in normal cells. Integrin αvβ6 is upregulated in several solid tumors, but is minimally expressed in normal epithelial cells, which suggests integrin αvβ6 as an attractive target antigen for CAR T cell immunotherapy in CCA. We investigated integrin αvβ6 expression in pathological tissue samples from patients with liver fluke-associated CCA. We then created CAR T cells targeting integrin αvβ6 and evaluated their anti-tumor activities against CCA cells. We found overexpression of the integrin αvβ6 protein in 23 of 30 (73.3%) CCA patient tissue samples. Significant association between high integrin αvβ6 expression and short survival time (p = 0.043) was also observed. Lentiviral constructs were engineered to encode CARs containing an integrin αvβ6-binding peptide (A20) derived from foot-and-mouth disease virus fused with a second-generation CD28/CD3ζ signaling domain (A20-2G CAR) or with a fourth-generation CD28/4-1BB/CD27/CD3ζ signaling domain (A20-4G CAR). The A20-2G and A20-4G CARs were highly expressed in primary human T cells transduced with the engineered lentiviruses, and they exhibited high levels of cytotoxicity against integrin αvβ6-positive CCA cells (p < 0.05). Interestingly, the A20-2G and A20-4G CAR T cells displayed anti-tumor function against integrin αvβ6-positive CCA tumor spheroids (p < 0.05). Upon specific antigen recognition, A20-4G CAR T cells produced a slightly lower level of IFN-γ, but exhibited higher proliferation than A20-2G CAR T cells. Thus, the A20-4G CAR T cells with lower level of cytokine production, but with higher proliferation represents a promising potential adoptive T cell therapy for integrin αvβ6-positive CCA.

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Section: Discussionmentioning

confidence: 99%

Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells

et al. 2021

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“…Based on our T cell studies, VISTA agonists likely would exert minimal inhibitory impact on activated CAR T cells directly. However, we understand that CAR T cells activate macrophages or neutrophils to cause organ damage and other adverse events ( 52 ). As a result, heightened cytokine production from myeloid cells likely contribute to CRS and agonistic targeting of VISTA may ameliorate the innate components of the CAR T induced CRS.…”

Section: Vista Induce Myeloid Reprogramming: Evidence For Profound Rementioning

confidence: 99%

VISTA: A Target to Manage the Innate Cytokine Storm

et al. 2021

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In recent years, the success of immunotherapy targeting immunoregulatory receptors (immune checkpoints) in cancer have generated enthusiastic support to target these receptors in a wide range of other immune related diseases. While the overwhelming focus has been on blockade of these inhibitory pathways to augment immunity, agonistic triggering via these receptors offers the promise of dampening pathogenic inflammatory responses. V-domain Ig suppressor of T cell activation (VISTA) has emerged as an immunoregulatory receptor with constitutive expression on both the T cell and myeloid compartments, and whose agonistic targeting has proven a unique avenue relative to other checkpoint pathways to suppress pathologies mediated by the innate arm of the immune system. VISTA agonistic targeting profoundly changes the phenotype of human monocytes towards an anti-inflammatory cell state, as highlighted by striking suppression of the canonical markers CD14 and Fcγr3a (CD16), and the almost complete suppression of both the interferon I (IFN-I) and antigen presentation pathways. The insights from these very recent studies highlight the impact of VISTA agonistic targeting of myeloid cells, and its potential therapeutic implications in the settings of hyperinflammatory responses such as cytokine storms, driven by dysregulated immune responses to viral infections (with a focus on COVID-19) and autoimmune diseases. Collectively, these findings suggest that the VISTA pathway plays a conserved, non-redundant role in myeloid cell function.

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“…An important aspect to consider in CAR-T cells is the potential side effects due to overstimulation and/or inadequate stimulation. Severe CRS (grades 3 or 4) is an important hallmark in CD19+ that can compromise efficacy and lead to life-threatening conditions 28,29 . Upon tumour cell encounter, CAR-T cells release different pro-inflammatory cytokines such as TNFα, IFN□, IL-1 and GM-CSF that leads to macrophage recruitment and activation causing a dangerous cytokine storm involving IL-6 and GM-CSF 30, 31 .…”

Section: Discussionmentioning

confidence: 99%

Physiological (TCR-like) regulated lentiviral vectors for the generation of improved CAR-T cells

Tristán‐Manzano

Maldonado‐Pérez

Justicia-Lirio

et al. 2021

Preprint

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BackgroundChimeric antigen receptor (CAR) T cells directed against CD19 have achieved impressive outcomes for the treatment of relapsed/refractory B lineage lymphoid neoplasms. However, CAR-T therapy still has important limitations due to severe side effects and the lack of efficiency in 40-50% of the patients. Most CARs-T products are generated using retroviral vectors with strong promoters. However, high CAR expression levels can lead to tonic signalling, premature exhaustion and over-stimulation of CAR-T cells, reducing efficacy and increasing side effects. TCR-like expression of the CAR through genome editing resulted in enhanced anti-tumour potency, reducing tonic signalling and improving CAR-T phenotype. In this manuscript, we searched for LVs that mimic the TCR expression pattern as a closer-to-clinic alternative for the generation of improved CAR-T cells.MethodsDifferent LVs containing viral and human promoters were analysed to select those that closely mimic a TCR-like kinetic profile upon T-cell activation. WAS gene proximal promoter-driven LVs (AW-LVs) were selected to express a second generation 4-1BB aCD19 CAR (ARI-0001) into T cells to generate AWARI CAR-T cells. TCR-like AWARI and EF1α-driven ARI CAR T cells were analysed for in vitro and in vivo killing efficiency using leukaemia and lymphoma cellular models. Tonic signalling, exhaustion markers and phenotype were determined by flow cytometry. Large-scale automated manufacturing of AWARI CAR-T cells was performed in a CliniMACs Prodigy bioreactor.ResultsOur data showed that LVs expressing the transgene through the WAS gene proximal promoter mimic very closely the TCR (CD3) expression pattern kinetic upon TCR stimulation or antigen encounter. Compared to EF1α-driven ARI CAR-T cells, AWARI CAR-T cells exhibited a higher proportion of naïve/stem cell memory T cells with less exhausted phenotype after efficient killing of CD19+ cells both in vitro and in vivo. AWARI CAR-T cells also showed lower tonic signalling and reduced secretion of pro-inflammatory cytokines and were efficiently manufactured in large-scale GMP-like conditions.ConclusionsWAS-gene-promoter driven LVs can be used to generate physiological 4-1BB-CAR-T cell products with lower tonic signalling, improved phenotype and a safer profile. We propose the use of TCR-like LVs as an alternative to strong-promoter driven LVs for the generation of CAR-T products.

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The model of cytokine release syndrome in CAR T-cell treatment for B-cell non-Hodgkin lymphoma

Cited by 98 publications

References 106 publications

Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells

Chimeric Antigen Receptor T Cells Targeting Integrin αvβ6 Expressed on Cholangiocarcinoma Cells

VISTA: A Target to Manage the Innate Cytokine Storm

Physiological (TCR-like) regulated lentiviral vectors for the generation of improved CAR-T cells

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