The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy

Bedoya, Felipe; Frigault, Matthew J.; Maus, Marcela V.

doi:10.1016/j.ymthe.2016.11.011

Cited by 38 publications

(55 citation statements)

References 56 publications

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“…However, by using two different target antigens, the rate of potential side effects of CAR‐T cell therapy, including cytokine release syndrome (CRS), severe neurotoxicity and on‐target/off‐tumor toxicities, may be enhanced as well . As the key cytokine in CRS is interleukin (IL)‐6, blocking of the IL‐6 receptor with the monoclonal antibody tocilizumab is the appropriate regimen to treat CRS .…”

Section: Effective Antigen Targetingmentioning

confidence: 99%

CAR‐T cell therapy in melanoma: A future success story?

Simon

Uslu

2018

Experimental Dermatology

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Chimeric antigen receptor (CAR)‐T cells are one of the impressive recent success stories of anti‐cancer immunotherapy. Especially in haematological malignancies, this treatment strategy has shown promising results leading to the recent approval of two CAR‐T cell constructs targeting CD19 in the United States and the European Union. After the huge success in haematological cancers, the next step will be the evaluation of its efficacy in different solid tumors, which is currently investigated in preclinical as well as clinical settings. A commonly examined tumor model in the context of immunotherapy is melanoma, since it is known for its immunogenic features. However, the first results of CAR‐T cell therapy in solid tumors did not reveal the same impressive outcomes that were observed in haematological malignancies, as engineered cells need to cope with several challenges. Obstacles include the lack of migration of CAR‐T cells from blood vessels to the tumor site as well as the immunosuppressive tumor microenvironment within solid tumors. Another hurdle is posed by the identification of an ideal target antigen to avoid on‐target/off‐tumor toxicities. Regarding immune escape mechanisms, which can be developed by tumor cells to bypass immune recognition, the observation of antigen loss should also be considered. This article gives an overview of the challenges displayed in CAR‐T cell therapy for the use in solid tumors and discusses different new strategies and approaches that deal with these problems in order to improve CAR‐T cell therapy, particularly for its use in melanoma.

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Section: Effective Antigen Targetingmentioning

confidence: 99%

CAR‐T cell therapy in melanoma: A future success story?

Simon

Uslu

2018

Experimental Dermatology

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“…60 Corticosteroids may impair CAR-T expansion and persistence, and are thus avoided in milder cases of CRS. 63,65 Although not yet evaluated in clinical trials, recent preclinical studies have suggested a potential benefit of the Bruton's tyrosine kinase inhibitor, ibrutinib, and the JAK/STAT pathway inhibitor, ruxolitinib, in reducing CAR-T-mediated cytokine release and preventing CRS. 66,67 Despite the use of tocilizumab and corticosteroids, severe CRS has led to several deaths in clinical trials of CD19-specific CAR-Ts, and 5 deaths due to unexpected severe neurologic toxicity recently prompted the discontinuation of a large phase II clinical trial in adult subjects with relapsed/refractory B-ALL.…”

Section: Toxicities Of Car T-cellsmentioning

confidence: 99%

“…71 The pathogenesis of the serious neurologic complications seen with certain CAR-T products remains unclear. 60,65 Severe encephalopathy is unfortunately unresponsive to steroids in most cases and thus predictive models 72 and alternative treatment strategies are needed.…”

Section: Toxicities Of Car T-cellsmentioning

confidence: 99%

Chimeric antigen receptor T-cells for B-cell malignancies

Lichtman

Dotti

2017

Translational Research

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The adoptive transfer of T-lymphocytes modified to express chimeric antigen receptors (CAR-Ts) has produced impressive clinical responses among patients with B-cell malignancies. This has led to a rapid expansion in the number of clinical trials over the past several years. Although CD19-specific CAR-Ts are the most extensively evaluated, CAR-Ts specific for other B-cell-associated targets have also shown promise. However, despite this success, toxicities associated with CAR-T administration remain a significant concern. There continues to be substantial heterogeneity among CAR-T products, and differences in both CAR designs and CAR-T production strategies can substantially affect clinical outcomes. Ongoing clinical studies will further elucidate these differences and many other innovative approaches are being evaluated at the preclinical level. In this review, we will discuss the background and rationale for the use of CAR-Ts, provide an overview of advances in the field, and examine the application of CAR-Ts to the treatment of B-cell malignancies, including a summary of clinical trials published to date.

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“…Potential toxicities and safety are a major concern when bringing novel engineered cell therapies to the clinic, recently reviewed in detail [27]. Cellular therapies with gene-modified cells that encode proteins with novel functions introduce potentially immunogenic novel protein sequences, for example when using antibody fragments derived from mouse antibodies, junctional regions of the various combined protein modules, or virus-derived 2A or protease sequences [27–29].…”

Section: Manipulating Receptor Signaling Through Modular Designmentioning

confidence: 99%

“…Cellular therapies with gene-modified cells that encode proteins with novel functions introduce potentially immunogenic novel protein sequences, for example when using antibody fragments derived from mouse antibodies, junctional regions of the various combined protein modules, or virus-derived 2A or protease sequences [27–29]. Even though these therapies are given to immunocompromised patients with limited capacity to mount immune responses, engineered CARTs have been rejected and even anaphylactic reactions have occurred in patients [30].…”

Section: Manipulating Receptor Signaling Through Modular Designmentioning

confidence: 99%

Reprogramming cellular functions with engineered membrane proteins

Arber

Young

Barth

2017

Current Opinion in Biotechnology

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Taking inspiration from Nature, synthetic biology utilizes and modifies biological components to expand the range of biological functions for engineering new practical devices and therapeutics. While early breakthroughs mainly concerned the design of gene circuits, recent efforts have focused on engineering signaling pathways to reprogram cellular functions. Since signal transduction across cell membranes initiates and controls intracellular signaling, membrane receptors have been targeted by diverse protein engineering approaches despite limited mechanistic understanding of their function. The modular architecture of several receptor families has enabled the empirical construction of chimeric receptors combining domains from distinct native receptors which have found successful immunotherapeutic applications. Meanwhile, progress in membrane protein structure determination, computational modeling and rational design promise to foster the engineering of a broader range of membrane receptor functions. Marrying empirical and rational membrane protein engineering approaches should enable the reprogramming of cells with widely diverse fine-tuned functions.

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The Flipside of the Power of Engineered T Cells: Observed and Potential Toxicities of Genetically Modified T Cells as Therapy

Cited by 38 publications

References 56 publications

CAR‐T cell therapy in melanoma: A future success story?

CAR‐T cell therapy in melanoma: A future success story?

Chimeric antigen receptor T-cells for B-cell malignancies

Reprogramming cellular functions with engineered membrane proteins

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