TGF‐β–responsive CAR‐T cells promote anti‐tumor immune function

Hou, Andrew J.; Chang, ZeNan; Lorenzini, Michael H.; Zah, Eugenia; Chen, Yvonne Y.

doi:10.1002/btm2.10097

Cited by 86 publications

(56 citation statements)

References 47 publications

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“…Such approaches will inform methods to enhance NK cell targeting and to stimulate or inhibit their functions in vivo and will lead to the development of novel clinical interventions (212, 213). For example, CARs have already been engineered for soluble growth factors, such as TGF-β, that function in T cells and promote anti-tumor responses in vivo (67, 214, 215).…”

Section: Discussionmentioning

confidence: 99%

The Natural Cytotoxicity Receptors in Health and Disease

2019

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The Natural Cytotoxicity Receptors (NCRs), NKp46, NKp44, and NKp30, were some of the first human activating Natural Killer (NK) cell receptors involved in the non-MHC-restricted recognition of tumor cells to be cloned over 20 years ago. Since this time many host- and pathogen-encoded ligands have been proposed to bind the NCRs and regulate the cytotoxic and cytokine-secreting functions of tissue NK cells. This diverse set of NCR ligands can manifest on the surface of tumor or virus-infected cells or can be secreted extracellularly, suggesting a remarkable NCR polyfunctionality that regulates the activity of NK cells in different tissue compartments during steady state or inflammation. Moreover, the NCRs can also be expressed by other innate and adaptive immune cell subsets under certain tissue conditions potentially conferring NK recognition programs to these cells. Here we review NCR biology in health and disease with particular reference to how this important class of receptors regulates the functions of tissue NK cells as well as confer NK cell recognition patterns to other innate and adaptive lymphocyte subsets. Finally, we highlight how NCR biology is being harnessed for novel therapeutic interventions particularly for enhanced tumor surveillance.

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Section: Discussionmentioning

confidence: 99%

The Natural Cytotoxicity Receptors in Health and Disease

2019

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“…Stimulating HLA‐A2+, CD8+ T cells with the mutated peptide generated a TCR clone which, when expressed on T cells, mediated cytoxicity against tumor cells harboring the same mutation . Moreover, some recent studies have developed CARs against soluble proteins, indicating the potential to target brain tumor‐specific secreted factors.…”

Section: Overcoming Tumor Heterogeneitymentioning

confidence: 99%

CAR T cells for brain tumors: Lessons learned and road ahead

Akhavan

Alizadeh

Wang

et al. 2019

Immunological Reviews

173

161

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Malignant brain tumors, including glioblastoma, represent some of the most difficult to treat of solid tumors. Nevertheless, recent progress in immunotherapy, across a broad range of tumor types, provides hope that immunological approaches will have the potential to improve outcomes for patients with brain tumors. Chimeric antigen receptors (CAR) T cells, a promising immunotherapeutic modality, utilizes the tumor targeting specificity of any antibody or receptor ligand to redirect the cytolytic potency of T cells. The remarkable clinical response rates of CD19‐targeted CAR T cells and early clinical experiences in glioblastoma demonstrating safety and evidence for disease modifying activity support the potential of further advancements ultimately providing clinical benefit for patients. The brain, however, is an immune specialized organ presenting unique and specific challenges to immune‐based therapies. Remaining barriers to be overcome for achieving effective CAR T cell therapy in the central nervous system (CNS) include tumor antigenic heterogeneity, an immune‐suppressive microenvironment, unique properties of the CNS that limit T cell entry, and risks of immune‐based toxicities in this highly sensitive organ. This review will summarize preclinical and clinical data for CAR T cell immunotherapy in glioblastoma and other malignant brain tumors, including present obstacles to advancement.

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“…Indeed, instead of becoming dysfunctional in the presence of TGF-β, T cells engineered to express a TGF-β-responsive CAR proliferate and produce Th1 cytokines such as IFN-γ, TNF-α, and IL-2 6 . Furthermore, TGF-β CAR-T cells can protect neighboring, tumor-specific T cells from TGF-βmediated immune suppression 7 . CARs targeting soluble ligands may also serve as reporters for the presence of their cognate ligand in the in vivo milieu, but this will likely be contingent on proper T-cell trafficking to the site(s) of interest and has yet to be experimentally validated.…”

Section: Applicationsmentioning

confidence: 99%

Engineering primary T cells with chimeric antigen receptors for rewired responses to soluble ligands

2020

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The expression of synthetic receptors in primary T cells enables the programming of user-defined responses when designing T-cell therapies. Chimeric antigen receptors (CARs) are synthetic receptors that have demonstrated efficacy in cancer therapy by targeting immobilized antigens on the surface of malignant cells. We have recently shown they can also rewire T-cell responses to soluble ligands. In contrast to other synthetic receptors, CARs are not only readily engineered by rational design, but also clinically translatable with robust function in primary human T cells. This protocol discusses design principles for CARs responsive to soluble ligands and delineates steps for producing T cells expressing synthetic receptors. Functional assays for quantifying the ability of CART cells to sense and respond to soluble ligands are also presented. This protocol provides a framework for proficient immune-cell researchers to test novel T-cell therapies targeting soluble ligands in under two weeks. KEYWORDS Chimeric antigen receptor, primary human T cells, soluble factors Related manuscripts: 1. Chang, Z. L. et al. Rewiring T-cell responses to soluble factors with chimeric antigen receptors.

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TGF‐β–responsive CAR‐T cells promote anti‐tumor immune function

Cited by 86 publications

References 47 publications

The Natural Cytotoxicity Receptors in Health and Disease

The Natural Cytotoxicity Receptors in Health and Disease

CAR T cells for brain tumors: Lessons learned and road ahead

Engineering primary T cells with chimeric antigen receptors for rewired responses to soluble ligands

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