Switching on the green light for chimeric antigen receptor T‐cell therapy

Mardiana, Sherly; Lai, Junyun; House, Imran G.; Beavis, Paul A.; Darcy, Phillip K.

doi:10.1002/cti2.1046

Cited by 12 publications

(12 citation statements)

References 136 publications

(260 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Therefore, enhancing tumor T cell infiltration is one way to improve cancer immunotherapy. This could imply (i) manipulation of the T cells themselves through their transduction with chemokine receptors promoting non-hematopoietic tissue colonization [139,140] or manipulation of TFs that regulate expression of these homing receptors [60]; (ii) depletion of specific TAM subsets that exert trophic and/or immune suppressive functions either by ablation [13] or inactivation using STAT3 inhibitors [27]. The enhanced killing of cancer cells together with the recruitment of fresh monocytes will favor the engagement of the host immune system thanks to the presentation of tumor-derived Ags by professional APCs such as dendritic cells and/or immature TAM.…”

Section: Discussionmentioning

confidence: 99%

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

Verdeil

Lawrence

Schmitt-Verhulst

et al. 2019

Cancers

View full text Add to dashboard Cite

Oncogene-induced STAT3-activation is central to tumor progression by promoting cancer cell expression of pro-angiogenic and immunosuppressive factors. STAT3 is also activated in infiltrating immune cells including tumor-associated macrophages (TAM) amplifying immune suppression. Consequently, STAT3 is considered as a target for cancer therapy. However, its interplay with other STAT-family members or transcription factors such as NF-κB has to be considered in light of their concerted regulation of immune-related genes. Here, we discuss new attempts at re-educating immune suppressive tumor-associated macrophages towards a CD8 T cell supporting profile, with an emphasis on the role of STAT transcription factors on TAM functional programs. Recent clinical trials using JAK/STAT inhibitors highlighted the negative effects of these molecules on the maintenance and function of effector/memory T cells. Concerted regulation of STAT3 and STAT5 activation in CD8 T effector and memory cells has been shown to impact their tumor-specific responses including intra-tumor accumulation, long-term survival, cytotoxic activity and resistance toward tumor-derived immune suppression. Interestingly, as an escape mechanism, melanoma cells were reported to impede STAT5 nuclear translocation in both CD8 T cells and NK cells. Ours and others results will be discussed in the perspective of new developments in engineered T cell-based adoptive therapies to treat cancer patients. function of tumor-associated macrophages (TAM) and (ii) for the regulation of T cell functions. As STAT TFs are key players in the regulation of functions of these immune cells, their manipulation can have a beneficial or detrimental effect on the anti-tumor response depending on the targeted cell type. Tumor-Induced Inflammation Drives Accumulation of Tumor-Infiltrating Myeloid CellsCytokine receptor-induced signaling sustains and amplifies the activation of STAT3, NF-κB and AP-1 in a positive amplification loop, fueling tumor-associated inflammation. As such, a core inflammation-related gene set regulated by STAT3, NF-κB and AP-1 has recently been proposed as an "inflammatory index" in breast cancer cell lines and patient samples [4]. Importantly, in correlation with this inflammatory index, this study reported a concerted regulation of (i) non-inflammatory genes related to angiogenesis, metastasis, and cell proliferation; (ii) tumor genome instability; and (iii) heterogeneity of the tumor microenvironment (TME), including the recruited immune cells. Remarkably, these co-regulated characteristics were found across several cancer types driven by distinct oncogenes [4].Tumor-derived cytokines have been linked to the accumulation of immune-suppressive myeloid cells including both myeloid-derived suppressor cells (MDSCs; IMCs) and tumor-associated macrophages (TAM). In both human and mouse melanomas, IMCs have an important role in malignant progression and evasion from anti-tumor immunity that is linked to the suppression of T cell responses [6][7][8][9]. While increased...

show abstract

Section: Discussionmentioning

confidence: 99%

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

Verdeil

Lawrence

Schmitt-Verhulst

et al. 2019

Cancers

View full text Add to dashboard Cite

show abstract

“…Birinapant also significantly enhanced CAR T cell therapy, resulting in prolonged survival and tumour regression in tumour bearing mice, and significantly enhanced tumour cell death in a patient-derived tumoroid model, compared to CAR T cell or birinapant monotherapy [87]. Importantly, the ability of SMs to senstitise antigen negative cells to TNF-mediated apoptosis, an effect known as bystander killing (Figure 2), may be an effective strategy to avoid antigen negative relapse following CAR T cell therapy [88]. Harnessing tumour-antigen specific CAR T cells as a vehicle to deliver TNF specifically to the tumour in combination with birinapant may have a significant therapeutic advantage.…”

Section: Role Of Smac-mimetics In T Cell-specific Immunotherapiesmentioning

confidence: 99%

The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy

Michie

Kearney

Hawkins

et al. 2020

Cells

View full text Add to dashboard Cite

One of the hallmarks of cancer cells is their ability to evade cell death via apoptosis. The inhibitor of apoptosis proteins (IAPs) are a family of proteins that act to promote cell survival. For this reason, upregulation of IAPs is associated with a number of cancer types as a mechanism of resistance to cell death and chemotherapy. As such, IAPs are considered a promising therapeutic target for cancer treatment, based on the role of IAPs in resistance to apoptosis, tumour progression and poor patient prognosis. The mitochondrial protein smac (second mitochondrial activator of caspases), is an endogenous inhibitor of IAPs, and several small molecule mimetics of smac (smac-mimetics) have been developed in order to antagonise IAPs in cancer cells and restore sensitivity to apoptotic stimuli. However, recent studies have revealed that smac-mimetics have broader effects than was first attributed. It is now understood that they are key regulators of innate immune signalling and have wide reaching immuno-modulatory properties. As such, they are ideal candidates for immunotherapy combinations. Pre-clinically, successful combination therapies incorporating smac-mimetics and oncolytic viruses, as with chimeric antigen receptor (CAR) T cell therapy, have been reported, and clinical trials incorporating smac-mimetics and immune checkpoint blockade are ongoing. Here, the potential of IAP antagonism to enhance immunotherapy strategies for the treatment of cancer will be discussed.

show abstract

“…The last few years have seen a full blossoming of creative applications of the basic CAR T cell approach [28]. The field has seen the introduction of CAR transgenes into different cell lineages, such as natural killer cells (NK [29–31];) and regulatory T cells (Tregs [32];), the further modification of the engineered gene products [5], the testing of “off the shelf” CAR T cells [33], and the initial applications to fields outside of immuno-oncology (see below).…”

Section: Introductionmentioning

confidence: 99%

Tuning the performance of CAR T cell immunotherapies

et al. 2019

View full text Add to dashboard Cite

BackgroundSimultaneous advances in gene editing, T cell engineering and biotechnology currently provide an opportunity for rapid progress in medicine. The approval of chimeric antigen receptor (CAR) T cell therapies by the US Food and Drug Administration (FDA) and the European Commission have generated substantial momentum for these first-in-class therapies to be used in patients with B cell malignancies.Main bodyConsiderable efforts focus on improved outcomes and reduced side effects of the newly approved therapies. Using innovative strategies, researchers aim to extend CAR T cell use to tackle difficulties inherent in solid tumors. Efforts are underway to broaden the applications of CAR T cells, and the strategy has been successful in chronic viral infections and preclinical models of autoimmunity. Research is in progress to generate “off-the-shelf” CAR T cells, an advance, which would greatly increase patient availability and reduce treatment cost.ConclusionsIn this thematic review, we highlight advances that may help develop genetically engineered cells into a new category of medical therapies.

show abstract

Switching on the green light for chimeric antigen receptor T‐cell therapy

Cited by 12 publications

References 136 publications

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

Targeting STAT3 and STAT5 in Tumor-Associated Immune Cells to Improve Immunotherapy

The Immuno-Modulatory Effects of Inhibitor of Apoptosis Protein Antagonists in Cancer Immunotherapy

Tuning the performance of CAR T cell immunotherapies

Contact Info

Product

Resources

About