Tunable control of CAR T cell activity through tetracycline mediated disruption of protein–protein interaction

Hotblack, Alastair; Kokalaki, Evangelia; Palton, Morgan J.; Cheung, Gordon Weng-Kit; Williams, I. P.; Manzoor, Somayya; Grothier, Thomas; Piapi, Alice; Fiaccadori, Valeria; Wawrzyniecka, Patrycja; Roddy, Harriet; Agliardi, Giulia; Roddie, Claire; Onuoha, Shimobi; Thomas, Simon; Cordoba, Shaun; Pulé, Martin

doi:10.1038/s41598-021-01418-9

Cited by 13 publications

(20 citation statements)

References 32 publications

(38 reference statements)

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“…(40,41) Fab-based CARs have been previously described (42) and their increased stability has been exploited to improve CAR performance. (43) With this structure, we were able to produce CARs capable of CD21-speci c lysis and cytokine release in vitro. We found that converting proximal targeting CARs to a Fab format reduced tonic signalling and improved performance, resulting in a nal aCD21 CAR candidate effective in clinically relevant in vivo models.…”

Section: Discussionmentioning

confidence: 99%

Anti-CD21 Chimeric Antigen Receptor T cells for the Treatment of T Cell Acute Lymphoblastic Leukemia

Maciocia

Burley

Hoekx

et al. 2022

Preprint

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Relapsed/refractory (R/r) T cell acute lymphoblastic leukemia (T-ALL) has a dismal prognosis, with an unmet need for effective novel therapies. The successes seen in chimeric antigen receptor (CAR)-T cell therapy for B-ALL have yet to be fully translated to T-ALL. Most strategies have targeted pan-T antigens (CD7, CD5) but these may be limited by T cell aplasia and fratricide, requiring elimination of CAR-T antigen expression during manufacture and salvage hematopoietic stem cell transplantation (HSCT). Here, we describe CD21 as a novel immunotherapeutic strategy for the treatment of T-ALL. CD21 is largely confined to malignant T cells with expression in 57% of diagnostic T-ALL but only on a minor fraction of mature T cells (10%). While anti-CD21 CAR-T targeting membrane distal epitopes were ineffective, CAR-T cells utilising a novel Fab-CAR architecture and binding to membrane proximal epitopes showed no fratricide and were potent against low antigen density cell line and patient-derived xenograft models of T-ALL in vitro and in vivo. Further, we showed that CD21 expression in T-ALL can be upregulated by inhibition of the PI3K/ axis. CD21 is a novel target for CAR-T cell therapy in T-ALL, avoiding the fratricide and T cell aplasia seen with many T-ALL CAR-T strategies.

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Section: Discussionmentioning

confidence: 99%

Anti-CD21 Chimeric Antigen Receptor T cells for the Treatment of T Cell Acute Lymphoblastic Leukemia

Maciocia

Burley

Hoekx

et al. 2022

Preprint

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“…Their results demonstrated that CD4 CAR T cells have robust antitumor activities in vivo, and CAR T cells were depleted 24 h after CAMPATH treatment in different organs. In addition, bridging to an allogeneic HSCT following CAR T-cell therapy and using short-lived effector cells instead of T cells have been shown to be valid methods to prevent T-cell aplasia, with both strategies succeeding in clinical studies [ 89 , 90 ].…”

Section: T-cell Aplasia and Proposed Solutionsmentioning

confidence: 99%

CAR T-Cell Immunotherapy Treating T-ALL: Challenges and Opportunities

Ren

Tong

et al. 2023

Vaccines

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T-cell acute lymphoblastic leukemia (T-ALL), a form of T-cell malignancy, is a typically aggressive hematological malignancy with high rates of disease relapse and a poor prognosis. Current guidelines do not recommend any specific treatments for these patients, and only allogeneic stem cell transplant, which is associated with potential risks and toxicities, is a curative therapy. Recent clinical trials showed that immunotherapies, including monoclonal antibodies, checkpoint inhibitors, and CAR T therapies, are successful in treating hematologic malignancies. CAR T cells, which specifically target the B-cell surface antigen CD19, have demonstrated remarkable efficacy in the treatment of B-cell acute leukemia, and some progress has been made in the treatment of other hematologic malignancies. However, the development of CAR T-cell immunotherapy targeting T-cell malignancies appears more challenging due to the potential risks of fratricide, T-cell aplasia, immunosuppression, and product contamination. In this review, we discuss the current status of and challenges related to CAR T-cell immunotherapy for T-ALL and review potential strategies to overcome these limitations.

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“…An alternative could be designing reversible off/on-switches that permit temporal control of CAR T cell activation and preserve antitumour function [138][139][140] . Several designs have been proposed to date, many of which rely on the administration of small molecules 109,141,142 or antibodies 143 , among other methods [144][145][146] .…”

Section: Review Articlementioning

confidence: 99%

Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

et al. 2022

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Therapies with genetically modified T cells that express chimeric antigen receptors (CARs) specific for CD19 or B cell maturation antigen (BCMA) are approved to treat certain B cell malignancies. However, translating these successes into treatments for patients with solid tumours presents various challenges, including the risk of clinically serious on-target, off-tumour toxicity (OTOT) owing to CAR T cellmediated cytotoxicity against non-malignant tissues expressing the target antigen. Indeed, severe OTOT has been observed in various CAR Review articlewe examine the implications of OTOT on the development of CAR T cell therapies targeting solid tumours, summarize OTOT evidence in preclinical and clinical studies, and discuss advances in CAR T cell engineering that might help to overcome OTOT in the clinic. Risks and mechanisms of OTOTOTOT stems from CAR T cell-mediated recognition and lysis of nonmalignant tissues expressing the target antigen, potentially causing severe adverse events 23,26 . Upon recognition of a target antigen, CAR T cell activation leads to the formation of an immune synapse between the CAR and the target cell 27 , triggering effector functions (Fig. 2). The release of perforin and granzymes 28 is assumed to be a principal mechanism of CAR T cell-mediated cytotoxicity. However, other mechanisms, such as upregulation of T cell-surface molecules to induce target apoptosis (such as FAS ligand) 29 or secretion of cytokines, including IFNγ and/or TNF, may also contribute to tissue destruction [29][30][31] (Fig. 2).To generate CAR T cells that are both safe and effective in patients with solid tumours, target antigen selection is crucial. Optimal antigen candidates, referred to as neoantigens, should be exclusively expressed on malignant cells and not on non-malignant cells. Such antigens could arise from tumour-specific non-synonymous mutations, insertions or deletions that alter the amino acid sequence of cell-surface proteins, aberrant expression of oncofetal antigens, or tumour-specific posttranslational modifications [32][33][34][35][36][37] . However, cell-surface neoantigens are rare, particularly in tumours with a low mutational burden 38 . EGFRvIII, found in 24-67% of glioblastomas, is one of the few identified examples 39,40 . Consequently, the majority of CAR T cell therapy targets for solid tumours are tumour-associated antigens (TAAs) that are also expressed on non-malignant tissues (Fig. 3).

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Tunable control of CAR T cell activity through tetracycline mediated disruption of protein–protein interaction

Cited by 13 publications

References 32 publications

Anti-CD21 Chimeric Antigen Receptor T cells for the Treatment of T Cell Acute Lymphoblastic Leukemia

Anti-CD21 Chimeric Antigen Receptor T cells for the Treatment of T Cell Acute Lymphoblastic Leukemia

CAR T-Cell Immunotherapy Treating T-ALL: Challenges and Opportunities

Overcoming on-target, off-tumour toxicity of CAR T cell therapy for solid tumours

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