Cancer immunotherapy with CAR-T cells – behold the future

Graham, Charlotte; Hewitson, Rebecca; Pagliuca, Antonio; Benjamin, Reuben

doi:10.7861/clinmedicine.18-4-324

Cited by 34 publications

(37 citation statements)

References 16 publications

(27 reference statements)

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“…The FDA has recently given approval to CD19 CAR T-cell therapy to treat B cell acute lymphoid leukemia (ALL) and NHL [237]. However, the manufacturing of autologous CAR T cells is logistically challenging and expensive [238]. On the other hand, allogenic CAR-modified NK cells are attractive contenders for targeting malignant cells in the absence of a prior antigen sensitization, and extensive research efforts are ongoing to generate an off-the-shelf cellular product [239].…”

Section: Genetic Modification Of Nk Cellsmentioning

confidence: 99%

Harnessing NK Cell Checkpoint-Modulating Immunotherapies

Chauhan

Koehl

Kloeß

2020

Cancers

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During the host immune response, the precise balance of the immune system, regulated by immune checkpoint, is required to avoid infection and cancer. These immune checkpoints are the mainstream regulator of the immune response and are crucial for self-tolerance. During the last decade, various new immune checkpoint molecules have been studied, providing an attractive path to evaluate their potential role as targets for effective therapeutic interventions. Checkpoint inhibitors have mainly been explored in T cells until now, but natural killer (NK) cells are a newly emerging target for the determination of checkpoint molecules. Simultaneously, an increasing number of therapeutic dimensions have been explored, including modulatory and inhibitory checkpoint molecules, either causing dysfunction or promoting effector functions. Furthermore, the combination of the immune checkpoint with other NK cell-based therapeutic strategies could also strengthen its efficacy as an antitumor therapy. In this review, we have undertaken a comprehensive review of the literature to date regarding underlying mechanisms of modulatory and inhibitory checkpoint molecules.

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Section: Genetic Modification Of Nk Cellsmentioning

confidence: 99%

Harnessing NK Cell Checkpoint-Modulating Immunotherapies

Chauhan

Koehl

Kloeß

2020

Cancers

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“…These engineered T cells not only have potent anti-tumour activity but also have a novel profile of toxic side effects. 43 T cells are collected from a patient's peripheral blood using an apheresis machine. These cells are then genetically modified in a laboratory to express an artificial chimeric antigen receptor (CAR).…”

Section: Targeted Therapies In MMmentioning

confidence: 99%

“…CARs chiefly consist of three components, an extracellular domain derived from a monoclonal antibody which binds to an antigen on the malignant cell, a transmembrane domain which anchors the CAR to the T cells and an intracellular T-cell activation domain, CD3ζ with or without a costimulatory domain, that confers the T cell with sustained anti-tumour activity (Figure 7). 43 Once the CAR-T cells have been made, they are allowed to replicate in vitro , and millions of copies are produced. Patients then receive immunosuppressive chemotherapy before the CAR-T cells are infused intravenously.…”

Section: Direction Of Future Treatmentsmentioning

confidence: 99%

Multiple myeloma: an overview of management

Bird

Boyd

2019

Palliat�Care

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Multiple myeloma represents 2% of all new cancer diagnoses in the United Kingdom and accounts for 2% of all cancer deaths. In the past few decades, there have been huge improvements in life expectancy which have been driven by novel therapeutic agents, autologous stem cell transplants and intensified supportive care. This review will discuss the pathogenesis of multiple myeloma, current management approaches and the direction of future treatments. In addition, this review will highlight the high burden of symptoms that patients experience and therefore the great benefits that can be gained from specialist palliative care input.

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“…Cellular therapies such as CART-cells have shown clinical efficacy against haematological malignancies and are approved for several leukaemias and lymphomas [1,2]. Despite efficacy seen in pre-clinical models, this success has not yet been matched for solid tumours and a suitable dosing strategy to maximise efficacy remains uncertain [3][4][5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

Quantifying the Limits of Immunotherapies in Mice and Men

Brown

Gaffney

Ager

et al. 2019

Preprint

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CART (Chimeric Antigen Receptor T)-cells are approved for treatment of several leukaemia and lymphoma indications. However, this therapeutic modality has not delivered comparable clinical efficacy for solid tumour indications despite promising preclinical outcomes in mouse solid tumour models. Lower rates of effective CART-cell delivery to solid tumours in humans as compared to human haematological malignancies and/or solid tumours in mice might partially explain these divergent outcomes. As the initial delivery of CART-cells to tumour tissue is mediated by the circulatory system, we developed in silico models of the human, rat and mouse circulatory systems. Model structure and parameterisation were informed by an extensive body of published comparative anatomical and physiological studies and associated experimental data. Models were used to estimate the species-dependent upper limit and variation of delivery rates of blood borne immune cells, such as T-and NK cells, to tumour tissue across different organs and species. Large cross-species differences in absolute delivery rates to organs were identified. Estimated maximum delivery rates were up to 10,000-fold greater in mice than humans, yet reported administered CART-cell doses were typically only 10-100 times lower in mice. This suggests that higher human CART-doses may be needed to drive efficacy comparable to that observed in preclinical solid tumour mice models. Accordingly, we posit that a more quantitative analysis of species-and organ-specific immune cell delivery rates and how they may be pharmacologically optimised will be key to unlocking the potential of engineered T-cells for solid tumours.

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Cancer immunotherapy with CAR-T cells – behold the future

Cited by 34 publications

References 16 publications

Harnessing NK Cell Checkpoint-Modulating Immunotherapies

Harnessing NK Cell Checkpoint-Modulating Immunotherapies

Multiple myeloma: an overview of management

Quantifying the Limits of Immunotherapies in Mice and Men

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