TRUCKS, the fourth‐generation CAR T cells: Current developments and clinical translation

Chmielewski, Markus; Abken, Hinrich

doi:10.1002/acg2.84

Cited by 107 publications

(95 citation statements)

References 57 publications

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“…Although externally-provided cues can be used to control transgene expression through specific promoters, the development of completely autonomous inducible systems is the focus of intense research efforts currently. In this direction, it should be noted that CAR T cells efficacy can be potentiated by combining the direct attack of the CAR T cells themselves along with the secretion of ectopic cytokines in order to boost the immune response against target components (CAR T fourth generation, TRUCK CAR) [ 122 , 123 ]. This is achieved by inserting cytokine transgenes under the control of a Nuclear Factor of Activated T-cells (NFAT)-inducible promoter, since CAR stimulation induces, phosphorylation of NFAT, which subsequently migrates to the nucleus and activates sensitive promoters inserted in the LV construct and hence, gene expression.…”

Section: Discussionmentioning

confidence: 99%

Toward Tightly Tuned Gene Expression Following Lentiviral Vector Transduction

Page

Fusil

Cosset

2020

Viruses

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Lentiviral vectors are versatile tools for gene delivery purposes. While in the earlier versions of retroviral vectors, transgene expression was controlled by the long terminal repeats (LTRs), the latter generations of vectors, including those derived from lentiviruses, incorporate internal constitutive or regulated promoters in order to regulate transgene expression. This allows to temporally and/or quantitatively control transgene expression, which is required for many applications such as for clinical applications, when transgene expression is required in specific tissues and at a specific timing. Here we review the main systems that have been developed for transgene regulated expression following lentiviral gene transfer. First, the induction of gene expression can be triggered either by external or by internal cues. Indeed, these regulated vector systems may harbor promoters inducible by exogenous stimuli, such as small molecules (e.g., antibiotics) or temperature variations, offering the possibility to tune rapidly transgene expression in case of adverse events. Second, expression can be indirectly adjusted by playing on inserted sequence copies, for instance by gene excision. Finally, synthetic networks can be developed to sense specific endogenous signals and trigger defined responses after information processing. Regulatable lentiviral vectors (LV)-mediated transgene expression systems have been widely used in basic research to uncover gene functions or to temporally reprogram cells. Clinical applications are also under development to induce therapeutic molecule secretion or to implement safety switches. Such regulatable approaches are currently focusing much attention and will benefit from the development of other technologies in order to launch autonomously controlled systems.

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Section: Discussionmentioning

confidence: 99%

Toward Tightly Tuned Gene Expression Following Lentiviral Vector Transduction

Page

Fusil

Cosset

2020

Viruses

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“…In this situation, tumor microenvironments are amended, and the lifespan of CAR T cells is prolonged. The clinical trials of this concept combining innate and adaptive immunity are still in cradle [ 24 ]. By synchronous installation of IL-2 receptor and binding site for the transcription factor STAT3 to the endodomain, vigorous JAK–STAT3/5 cytokine, cascade can be instigated in local tumor environment and thus minimizes systemic inflammation [ 25 ] ( Figure 1 ).…”

Section: Chimeric Antigen Receptor (Car) T-cell Therapymentioning

confidence: 99%

New Era of Immunotherapy in Pediatric Brain Tumors: Chimeric Antigen Receptor T-Cell Therapy

Lin

Chen

et al. 2021

IJMS

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Immunotherapy, including chimeric antigen receptor (CAR) T-cell therapy, immune checkpoint inhibitors, cancer vaccines, and dendritic cell therapy, has been incorporated as a fifth modality of modern cancer care, along with surgery, radiation, chemotherapy, and target therapy. Among them, CAR T-cell therapy emerges as one of the most promising treatments. In 2017, the first two CAR T-cell drugs, tisagenlecleucel and axicabtagene ciloleucel for B-cell acute lymphoblastic leukemia (ALL) and diffuse large B-cell lymphoma (DLBCL), respectively, were approved by the Food and Drug Administration (FDA). In addition to the successful applications to hematological malignancies, CAR T-cell therapy has been investigated to potentially treat solid tumors, including pediatric brain tumor, which serves as the leading cause of cancer-associated death for children and adolescents. However, the employment of CAR T-cell therapy in pediatric brain tumors still faces multiple challenges, such as CAR T-cell transportation and expansion through the blood–brain barrier, and identification of the specific target antigen on the tumor surface and immunosuppressive tumor microenvironment. Nevertheless, encouraging outcomes in both clinical and preclinical trials are coming to light. In this article, we outline the current propitious progress and discuss the obstacles needed to be overcome in order to unveil a new era of treatment in pediatric brain tumors.

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“…The fourth generation of CAR-T cells, also known as T cells redirected for universal cytokine killing (TRUCKs), contains an activated T cell nuclear factor transcriptional counterpart that helps them secrete specific cytokines (interleukin-12). These cytokines modify the tumor microenvironment (one of the significant causes of resistance to CAR-T cells of earlier generations) and reconstitute the immune system by recruiting and activating other immune cells to induce an immune response, creating a hostile environment for tumor survival [ 13 , 27 ].…”

Section: Reviewmentioning

confidence: 99%

The Role of Chimeric Antigen Receptor-T Cell Therapy in the Treatment of Hematological Malignancies: Advantages, Trials, and Tribulations, and the Road Ahead

Reddy¹,

Llukmani²,

Hashim³

et al. 2021

Cureus

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Immunotherapy is the upcoming trend in cancer treatment. Traditional cancer treatment methods include surgical resection, radiotherapy, chemotherapy, small molecule targeted drugs, monoclonal antibodies, and hematopoietic stem cell transplantation (HSCT). Surgical resection is useful for early-stage patients but not for metastatic cancer cells; radiotherapy and chemotherapy are more common but produce substantial damage to normal tissues and have poor selectivity. Targeted drugs, including monoclonal antibodies, have better comprehensive efficacy but can also encourage gene mutation of tumor cells and drug tolerance. HSCT is effective, but choosing a donor is often difficult, and the graft is also prone to rejection. Thus, chimeric antigen receptor (CAR)-T cell therapy, a form of cellular/adoptive immunotherapy, is at the forefront of cancer therapy treatments due to its sustained remission, fewer side effects, and a better quality of life. CAR-T cell therapy involves genetically modifying the T cells and multiplying their numbers to kill cancer cells. This review article gives an insight into how the CAR-T cells have evolved from simple T cells with modest immune function to genetically engineered robust counterparts that brought great hope in the treatment of hematological malignancies. Much research has been undertaken during the past decade to design and deliver CAR-T cells. This has led to successful outcomes in leukemias, lymphomas, and multiple myeloma, paving the way for expanding CAR therapy. Despite tremendous progress, CAR-T cell therapies are faced with many challenges. Areas for improvement include limited T cell persistence, tumor escape, immunosuppressive components in the tumor microenvironment, cancer relapse rate, manufacturing time, and production cost. In this manuscript, we summarize the innovations in the design and delivery of CAR technologies, their applications in hematological malignancies, limitations to its widespread application, latest developments, and the future scope of research to counter the challenges and improve its effectiveness and persistence.

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TRUCKS, the fourth‐generation CAR T cells: Current developments and clinical translation

Cited by 107 publications

References 57 publications

Toward Tightly Tuned Gene Expression Following Lentiviral Vector Transduction

Toward Tightly Tuned Gene Expression Following Lentiviral Vector Transduction

New Era of Immunotherapy in Pediatric Brain Tumors: Chimeric Antigen Receptor T-Cell Therapy

The Role of Chimeric Antigen Receptor-T Cell Therapy in the Treatment of Hematological Malignancies: Advantages, Trials, and Tribulations, and the Road Ahead

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