Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE)

George, P. J. M.; Dasyam, Nathaniel; Giunti, Giulia; Mester, Brigitta; Bauer, Evelyn; Andrews, Bethany; Perera, Travis; Ostapowicz, Tess; Frampton, Chris; Li, Peng; Ritchie, David; Bollard, Catherine M.; Hermans, Ian F.; Weinkove, Robert

doi:10.1136/bmjopen-2019-034629

Cited by 32 publications

(32 citation statements)

References 32 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“… 19 , 20 In addition, third-generation CAR T-cells have been shown to enhance efficacy, proliferation, and cytokine production in the clinic. 21 However, there is contradictory evidence as to whether second- or third-generation CAR T-cells produce more significant responses in patients. 21 , 22 …”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy

Hawkins¹,

D'Souza²,

Klampatsa³

2021

BTT

View full text Add to dashboard Cite

Chimeric antigen receptor (CAR) T-cell therapy engineers T-cells to express a synthetic receptor which redirects effector function to the tumor, to improve efficacy and reduce toxicities associated with conventional treatments, such as radiotherapy and chemotherapy. This approach has proved effective in treating hematological malignancies; however, the same effects have not been observed in solid tumors. The immunosuppressive tumor microenvironment (TME) creates a significant barrier to solid tumor efficacy and reduces the anti-cancer activity of endogenous tumor-resident immune cells, enabling cancer progression. In recent years, researchers have attempted to enhance CAR T-cell function in the TME by engineering the cells to express various proteins alongside the CAR. Examples of this engineering include inducing CAR T-cells to secrete cytokines or express cytokine receptors to modulate the cytokine milieu of the TME. Alternatively, the CAR T-cell may secrete antibody-like proteins to target a range of tumor antigens. Collectively, these methods are termed armored CAR T-cell therapy, and in this review, we will discuss the range of armored CAR T-cell approaches which have been investigated to date.

show abstract

Section: Introductionmentioning

confidence: 99%

“… 21 However, there is contradictory evidence as to whether second- or third-generation CAR T-cells produce more significant responses in patients. 21 , 22 …”

Section: Introductionmentioning

confidence: 99%

Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy

Hawkins¹,

D'Souza²,

Klampatsa³

2021

BTT

View full text Add to dashboard Cite

show abstract

“…OX40 co-stimulatory signaling effectively represses IL-10 secretion, and contributes to counteract self-repression, thus facilitates a prolonged CAR T cells response [31,38]. Toll-like receptor 2 (TLR2)-incorporated CAR T cells demonstrate improved expansion and persistence due to the capacity of generating memory T cells, expressing pro-survival proteins and abolishing the suppression of regulatory T cells [39][40][41]. CD40 signaling contributes to memory formation and rescuing T cells from exhaustion [42,43].…”

Section: Transmembrane and Intracellular Domainsmentioning

confidence: 99%

Engineering better chimeric antigen receptor T cells

2020

View full text Add to dashboard Cite

CD19-targeted CAR T cells therapy has shown remarkable efficacy in treatment of B cell malignancies. However, relapse of primary disease remains a major obstacle after CAR T cells therapy, and the majority of relapses present a tumor phenotype with retention of target antigen (antigen-positive relapse), which highly correlate with poor CAR T cells persistence. Therefore, study on factors and mechanisms that limit the in vivo persistence of CAR T cells is crucial for developing strategies to overcome these limitations. In this review, we summarize the rapidly developing knowledge regarding the factors that influence CAR T cells in vivo persistence and the underlying mechanisms. The factors involve the CAR constructs (extracellular structures, transmembrane and intracellular signaling domains, as well as the accessory structures), activation signaling (CAR signaling and TCR engagement), methods for in vitro culture (T cells collection, purification, activation, gene transduction and cells expansion), epigenetic regulations, tumor environment, CD4/CD8 subsets, CAR T cells differentiation and exhaustion. Of note, among these influence factors, CAR T cells differentiation and exhaustion are identified as the central part due to the fact that almost all factors eventually alter the state of cells differentiation and exhaustion. Moreover, we review the potential coping strategies aiming at these limitations throughout this study.

show abstract

“…CART therapy involves genetically modified patient T cells with chimeric antigen receptors that recognize specific antigens on the tumor cell surface. The antitumor efficacy of immunotherapy against hematologic cancers has been extended to other tumors [ 99 , 100 , 101 ]. Among diverse potential targets, such as CD19 for B-cell malignancies, GD2, a disialoganglioside glycolipid, was identified as a tumor antigen more than 30 years ago [ 102 ].…”

Section: Active Modulation Of Lipid Metabolism To Improve Car T Cementioning

confidence: 99%

Lipidomic-Based Advances in Diagnosis and Modulation of Immune Response to Cancer

Balgoma

Montero

2020

Metabolites

View full text Add to dashboard Cite

While immunotherapies for diverse types of cancer are effective in many cases, relapse is still a lingering problem. Like tumor cells, activated immune cells have an anabolic metabolic profile, relying on glycolysis and the increased uptake and synthesis of fatty acids. In contrast, immature antigen-presenting cells, as well as anergic and exhausted T-cells have a catabolic metabolic profile that uses oxidative phosphorylation to provide energy for cellular processes. One goal for enhancing current immunotherapies is to identify metabolic pathways supporting the immune response to tumor antigens. A robust cell expansion and an active modulation via immune checkpoints and cytokine release are required for effective immunity. Lipids, as one of the main components of the cell membrane, are the key regulators of cell signaling and proliferation. Therefore, lipid metabolism reprogramming may impact proliferation and generate dysfunctional immune cells promoting tumor growth. Based on lipid-driven signatures, the discrimination between responsiveness and tolerance to tumor cells will support the development of accurate biomarkers and the identification of potential therapeutic targets. These findings may improve existing immunotherapies and ultimately prevent immune escape in patients for whom existing treatments have failed.

show abstract

Third-generation anti-CD19 chimeric antigen receptor T-cells incorporating a TLR2 domain for relapsed or refractory B-cell lymphoma: a phase I clinical trial protocol (ENABLE)

Cited by 32 publications

References 32 publications

Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy

Armored CAR T-Cells: The Next Chapter in T-Cell Cancer Immunotherapy

Engineering better chimeric antigen receptor T cells

Lipidomic-Based Advances in Diagnosis and Modulation of Immune Response to Cancer

Contact Info

Product

Resources

About