The Association Between Glucocorticoid Administration and the Risk of Impaired Efficacy of Axicabtagene Ciloleucel Treatment: A Systematic Review

Sun, Zhenliang; Xun, RenDe; Liu, MengSi; Wu, Xinxin; Qu, Hongtao

doi:10.3389/fimmu.2021.646450

Cited by 14 publications

(16 citation statements)

References 45 publications

(70 reference statements)

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“…Dex is used to treat several different kinds of cancer, such as multiple myeloma and glioblastoma (45, 46), as well as to treat immune-related toxicities associated with CAR T cell therapy. While there is concern that dex may decrease the function and persistence of CAR T cells (18, 19), we found that dex enhanced the efficacy of CAR T cells in our model ( Figure 7, Figure S7 ). These results are supported by the recent clinical observation that CAR T cells had better expansion and persistence in patients who received dex compared patients who did not receive dex (20).…”

Section: Discussionmentioning

confidence: 66%

“…Binding of GCs to the glucocorticoid receptor (GR) causes GR dimerization and translocation to the nucleus, where GRs can modulate expression of genes that contain a glucocorticoid response element (GRE) (5)(6)(7)(8)(9), including those involved in T cell proliferation and survival. In general, GCs are not routinely given to patients receiving CAR T cells, except to treat severe neurotoxicity associated with CAR T cell therapy, due to the concern that GCs may dampen CAR T cell activity and persistence (18,19). However, recent evaluation of clinical data suggests that treatment with GCs, including the synthetic GC dexamethasone (dex), does not affect proliferation or persistence of CAR T cells (20).…”

Section: Introductionmentioning

confidence: 99%

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Dexamethasone Enhances CAR T Cell Persistence and Function by Upregulating Interleukin 7 Receptor

Munoz

Urak

Taus

et al. 2022

Preprint

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Dexamethasone (dex) is a glucocorticoid that is a mainstay for treatment of inflammatory pathologies, including immunotherapy-associated toxicities. Dex suppresses the endogenous immune response and is also believed to suppress the function of chimeric antigen receptor (CAR) T cells. However, recent reports observed higher CAR T cell numbers in patients treated with dex, highlighting the rationale for interrogating the specific effects of dex on CAR T cells. Here, we found that dex did not inhibit CAR T cell expansion or function. A single dose of dex during the manufacturing process upregulated the pro-persistence interleukin 7 receptor alpha (IL7Ra) on CAR T cells and induced expression of genes involved in activation, migration, and persistence. The ex vivo upregulation of IL7Ra induced by dex significantly enhanced CAR T cell persistence and anti-tumor efficacy in vivo when combined with exogenous IL-7. Moreover, the combination of dex and IL-7 resulted in increased persistence of CAR T cells and led to complete remission of mice. Overall, our studies in both in vitro and in vivo treatment support a positive role of dex on CAR T cell potency and provide insight into the application of glucocorticoids in cellular anti-cancer therapy.

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Section: Discussionmentioning

confidence: 66%

Section: Introductionmentioning

confidence: 99%

Dexamethasone Enhances CAR T Cell Persistence and Function by Upregulating Interleukin 7 Receptor

Munoz

Urak

Taus

et al. 2022

Preprint

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“…Protected by copyright. http://jitc.bmj.com/ safety outcomes for a specific CAR-T cell therapy or a specific indication, [82][83][84][85][86][87][88][89] but the correlation between dose and related factors and response was not studied. To derive from the combined knowledge of all relevant clinical studies, all CAR-T cells therapies for hematological cancers were analyzed together for correlations and then analyzed separately based on target antigens as well as intracellular domains.…”

Section: Discussionmentioning

confidence: 99%

Dose–response correlation for CAR-T cells: a systematic review of clinical studies

Rotte¹,

Frigault

Ansari³

et al. 2022

J Immunother Cancer

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The potential of chimeric antigen receptor (CAR) T cells to successfully treat hematological cancers is widely recognized. Multiple CAR-T cell therapies are currently under clinical development, with most in early stage, during which dose selection is a key goal. The objective of this review is to address the question of dose-dependent effects on response and/or toxicity from available CAR-T cell clinical trial data. For that purpose, systematic literature review of studies published between January 2010 and May 2022 was performed on PubMed and Embase to search clinical studies that evaluated CAR-T cells for hematological cancers. Studies published in English were considered. Studies in children (age <18 years), solid tumors, bispecific CAR-T cells and CAR-T cell cocktails were excluded. As a result, a total of 74 studies met the inclusion criteria. Thirty-nine studies tested multiple dose levels of CAR-T cells with at least >1 patient at each dose level. Thirteen studies observed dose-related increase in disease response and 23 studies observed dose-related increase in toxicity across a median of three dose levels. Optimal clinical efficacy was seen at doses 50–100 million cells for anti-CD19 CAR-T cells and >100 million cells for anti-BCMA CAR-T cells in majority of studies. The findings suggest, for a given construct, there exists a dose at which a threshold of optimal efficacy occurs. Dose escalation may reveal increasing objective response rates (ORRs) until that threshold is reached. However, when ORR starts to plateau despite increasing dose, further dose escalation is unlikely to result in improved ORR but is likely to result in higher incidence and/or severity of mechanistically related adverse events.

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“…Corticosteroids are used for CRS resistant cases and for CAR-related neurological complications (32). Some reports indicate that corticosteroids can negatively affect CAR T-cell persistence and function (39,40), while other reports do not link steroids to poorer outcomes (41). Nonetheless, CAR T-cell therapies that do not induce deleterious, systemic inflammation may prove more efficacious than existing ones.…”

Section: Discussionmentioning

confidence: 99%

Murine CAR19 Tregs suppress acute graft-versus-host disease and maintain graft-versus-tumor responses

Bolivar-Wagers¹,

Loschi²,

Jin³

et al. 2022

JCI Insight

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) efficacy is complicated by graftversus-host disease (GVHD), a leading cause of morbidity and mortality. Regulatory T-cells (Tregs) have shown efficacy in preventing GVHD. However, high Treg doses are often required, necessitating substantial ex vivo or in vivo expansion that may diminish suppressor function. To enhance in vivo suppressor function, murine Treg were transduced to express an anti-human CD19scFv chimeric antigen receptor (hCAR19) and infused into lethally irradiated hCD19 transgenic recipients for allo-HSCT. Compared to recipients receiving control transduced Tregs, those receiving hCAR19 Tregs had a significant decrease in acute GVHD lethality. Recipient hCD19 B-cells and murine hCD19TBL12 luc lymphoma cells were both cleared by allogeneic hCAR19 Tregs indicative of graft-versus tumor (GVT) maintenance and potentiation. Mechanistically, hCAR19 Tregs killed syngeneic hCD19+ but not hCD19-murine TBL12 luc cells in vitro in a perforin-dependent, granzyme B-independent manner. Importantly, cyclophosphamide treated hCD19 transgenic mice given hCAR19 cytotoxic T-lymphocytes without allo-HSCT experienced rapid lethality due to systemic toxicity that has been associated with proinflammatory cytokine release; in contrast, hCAR19 Treg suppressor function enabled avoidance of this severe complication. In conclusion, hCAR19 Tregs are a novel and effective strategy to suppress GVHD without loss of GVT responses. Treg redirected through bispecific T-cell engagers (BiTEs) maintained suppression while killing antigen expressing tumor cells in a perforin dependent, partially GzB dependent manner (30). Whereas MacDonald et al (2016) reported human HLA-A2 specific CAR Treg killing of HLA-A2+ targets in vitro (17), to date only Boroughs et al (2019) has reported in vitro and in vivo killing by human CAR19 Tregs (31). This group demonstrated that human CAR19 Tregs killed CD19+ targets in vitro via the perforin-granzyme pathway, with measurable but low killing of antigenexpressing targets in vivo using a skin allograft model (31). CAR Tregs could theoretically engage in targeted killing while simultaneously performing immunosuppression. Activation of conventional CAR19 T-cells by CD19+ targets triggers the release of proinflammatory cytokines (e.g., TNFα, IFNγ) which, in turn, induce endogenous myeloid and endothelial cells to secrete additional proinflammatory cytokines (e.g., IL-1ß, IL-6). These amplifying waves of inflammation cause toxicities such as cytokine release syndrome (CRS), an acute systemic inflammatory response with fever and multi-organ dysfunction, and an immune effector cell-associated neurotoxicity syndrome (ICANS) (32-34). Because CAR19 Tregs can kill CD19+ targets directly, we reasoned CAR19 Tregs would have anti-tumor efficacy in vivo.Because Tregs also blunt immune activation of bystander cells, we hypothesized that CAR19 Tregs would be superior to conventional CAR19 T-cells by reducing toxicities caused by systemic inflammation. To tes...

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The Association Between Glucocorticoid Administration and the Risk of Impaired Efficacy of Axicabtagene Ciloleucel Treatment: A Systematic Review

Cited by 14 publications

References 45 publications

Dexamethasone Enhances CAR T Cell Persistence and Function by Upregulating Interleukin 7 Receptor

Dexamethasone Enhances CAR T Cell Persistence and Function by Upregulating Interleukin 7 Receptor

Dose–response correlation for CAR-T cells: a systematic review of clinical studies

Murine CAR19 Tregs suppress acute graft-versus-host disease and maintain graft-versus-tumor responses

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