Counteracting CAR T cell dysfunction

Poorebrahim, Mansour; Melief, Jeroen; Coaña, Yago Pico de; Wickström, Stina L.; Cid-Arregui, Ángel; Kiessling, Rolf

doi:10.1038/s41388-020-01501-x

Cited by 96 publications

(71 citation statements)

References 142 publications

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“…Despite high proliferative capacity being lost early as well, exhausted T-cells are still capable of limited proliferation when stimulated in vivo. During the exhaustion progression, the chronic TCR stimulation leads to modifications in T-cell receptor (TCR)-dependent signaling pathways, such as those mediated by nuclear factor of activated T-cells (NFAT) [ 122 , 123 , 124 ].…”

Section: Factors Influencing T-cell Persistence In Clinical Settingsmentioning

confidence: 99%

Improving CAR T-Cell Persistence

Pietrobon

Todd

Goswami

et al. 2021

IJMS

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Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.

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Section: Factors Influencing T-cell Persistence In Clinical Settingsmentioning

confidence: 99%

Improving CAR T-Cell Persistence

Pietrobon

Todd

Goswami

et al. 2021

IJMS

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“…One factor which may currently limit the use of CAR-T strategies in solid tumors could be the issue of T-Cell exhaustion [ 128 ]. However, recent studies suggest that checkpoint inhibitors may be a mechanism for improving the potency of CAR-T cell therapies in this regard [ 129 – 131 ], and other approaches such as co-stimulation induction and cytokine based approaches may also have merit [ 128 ].…”

Section: Beyond Checkpoint Inhibitorsmentioning

confidence: 99%

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

Gray

2021

BMC Pulm Med

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Background The role of immunotherapy in cancer is now well-established, and therapeutic options such as checkpoint inhibitors are increasingly being approved in many cancers such as non-small cell lung cancer (NSCLC). Malignant pleural mesothelioma (MPM) is a rare orphan disease associated with prior exposure to asbestos, with a dismal prognosis. Evidence from clinical trials of checkpoint inhibitors in this rare disease, suggest that such therapies may play a role as a treatment option for a proportion of patients with this cancer. Main text While the majority of studies currently focus on the established checkpoint inhibitors (CTLA4 and PD1/PDL1), there are many other potential checkpoints that could also be targeted. In this review I provide a synopsis of current clinical trials of immunotherapies in MPM, explore potential candidate new avenues that may become future targets for immunotherapy and discuss aspects of immunotherapy that may affect the clinical outcomes of such therapies in this cancer. Conclusions The current situation regarding checkpoint inhibitors in the management of MPM whilst encouraging, despite impressive durable responses, immune checkpoint inhibitors do not provide a long-term benefit to the majority of patients with cancer. Additional studies are therefore required to further delineate and improve our understanding of both checkpoint inhibitors and the immune system in MPM. Moreover, many new potential checkpoints have yet to be studied for their therapeutic potential in MPM. All these plus the existing checkpoint inhibitors will require the development of new biomarkers for patient stratification, response and also for predicting or monitoring the emergence of resistance to these agents in MPM patients. Other potential therapeutic avenues such CAR-T therapy or treatments like oncolytic viruses or agents that target the interferon pathway designed to recruit more immune cells to the tumor also hold great promise in this hard to treat cancer.

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“…For instance, the level of CXCL8/IL-8 is increased in the melanoma tumor microenvironment, and engineered MAGR-A3 TCR-T cells expressing CXCR2 have shown higher infiltration in xenograft murine models [26]. Immune checkpoint inhibitors can also increase CAR T cells' efficacy and hinder the immune-suppressive tumor niche [27]. Besides that, the suppressive extracellular matrix (ECM) of tumors can be overcome by the expression of degrading enzymes such as Heparanase in CAR T cells [28], which can be applicable for TCR-CAR-based adoptive therapies.…”

Section: Adoptive Therapies Targeting Neoepitopesmentioning

confidence: 99%

TCR-like CARs and TCR-CARs targeting neoepitopes: an emerging potential

et al. 2021

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Neoepitopes or neoantigens are a spectrum of unique mutations presented in a particular patient’s tumor. Neoepitope-based adoptive therapies have the potential of tumor eradication without undue damaging effect on normal tissues. In this context, methods based on the T cell receptor (TCR) engineering or chimeric antigen receptors (CARs) have shown great promise. This review focuses on the TCR-like CARs and TCR-CARs directed against tumor-derived epitopes, with a concerted view on neoepitopes. We also address the current limitations of the field to know how to harness the full benefits of this approach and thereby design a sustained and specific antitumor therapy.

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Counteracting CAR T cell dysfunction

Cited by 96 publications

References 142 publications

Improving CAR T-Cell Persistence

Improving CAR T-Cell Persistence

Emerging avenues in immunotherapy for the management of malignant pleural mesothelioma

TCR-like CARs and TCR-CARs targeting neoepitopes: an emerging potential

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