Enhancing the effectiveness of γδ T cells by mRNA transfection of chimeric antigen receptors or bispecific T cell engagers

Becker, Scott A.; Petrich, Brian G.; Yu, Bing; Knight, Kristopher A.; Brown, Harrison C.; Raikar, Sunil S.; Doering, Christopher B.; Spencer, H. Trent

doi:10.1016/j.omto.2023.05.007

Cited by 10 publications

(17 citation statements)

References 61 publications

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“…γδ T-cell expansions were performed based on our previously published GMP-compliant protocol, which has been well-described and utilized in several publications from our group ( 22 , 36 , 39 , 46 ). Whole blood was obtained from healthy donors through the Children’s Clinical Translational Discovery Core at Emory University, under approved Emory University Institutional Review Board (IRB) protocol, or from Expression Therapeutics LLC (Atlanta, GA, USA).…”

Section: Methodsmentioning

confidence: 99%

“…Alternatively, synthetic ABPs, such as isopentenyl pyrophosphate (IPP) and IL-2, have been employed to expand Vγ9Vδ2 T cells ( 27 , 33 , 34 ). In addition, ex vivo -expanded Vγ9Vδ2 T cells can be engineered to express chimeric antigen receptors (CARs), which do not interfere with cellular innate killing or antigen-presenting capabilities ( 35 ), or bispecific T-cell engagers, for example, targeting CD19, a marker of B-cell malignancies, and have shown effective killing of CD19 + cell lines in vitro and in vivo ( 36 , 37 ). In addition, non-signaling CARs were generated that activate alternate killing mechanisms of the engineered cells, such as through the receptor CD314 (NKG2D) ( 38 ).…”

Section: Introductionmentioning

confidence: 99%

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Directing the migration of serum-free, ex vivo-expanded Vγ9Vδ2 T cells

Parwani,

Branella,

Burnham

et al. 2024

Front. Immunol.

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Vγ9Vδ2 T cells represent a promising cancer therapy platform because the implementation of allogenic, off-the-shelf product candidates is possible. However, intravenous administration of human Vγ9Vδ2 T cells manufactured under good manufacturing practice (GMP)-compliant, serum-free conditions are not tested easily in most mouse models, mainly because they lack the ability to migrate from the blood to tissues or tumors. We demonstrate that these T cells do not migrate from the circulation to the mouse bone marrow (BM), the site of many malignancies. Thus, there is a need to better characterize human γδ T-cell migration in vivo and develop strategies to direct these cells to in vivo sites of therapeutic interest. To better understand the migration of these cells and possibly influence their migration, NSG mice were conditioned with agents to clear BM cellular compartments, i.e., busulfan or total body irradiation (TBI), or promote T-cell migration to inflamed BM, i.e., incomplete Freund’s adjuvant (IFA), prior to administering γδ T cells. Conditioning with TBI, unlike busulfan or IFA, increases the percentage and number of γδ T cells accumulating in the mouse BM, and cells in the peripheral blood (PB) and BM display identical surface protein profiles. To better understand the mechanism by which cells migrate to the BM, mice were conditioned with TBI and administered γδ T cells or tracker-stained red blood cells. The mechanism by which γδ T cells enter the BM after radiation is passive migration from the circulation, not homing. We tested if these ex vivo-expanded cells can migrate based on chemokine expression patterns and showed that it is possible to initiate homing by utilizing highly expressed chemokine receptors on the expanded γδ T cells. γδ T cells highly express CCR2, which provides chemokine attraction to C-C motif chemokine ligand 2 (CCL2)-expressing cells. IFNγ-primed mesenchymal stromal cells (MSCs) (γMSCs) express CCL2, and we developed in vitro and in vivo models to test γδ T-cell homing to CCL2-expressing cells. Using an established neuroblastoma NSG mouse model, we show that intratumorally-injected γMSCs increase the homing of γδ T cells to this tumor. These studies provide insight into the migration of serum-free, ex vivo-expanded Vγ9Vδ2 T cells in NSG mice, which is critical to understanding the fundamental properties of these cells.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Directing the migration of serum-free, ex vivo-expanded Vγ9Vδ2 T cells

Parwani,

Branella,

Burnham

et al. 2024

Front. Immunol.

Self Cite

View full text Add to dashboard Cite

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“…Owing to the deficit of tumor-specific antigens, lineage-specific antigens have been a key focus in CAR T cell development. Under investigation are promising candidates like CD19 ( 153 , 154 ), GD2 ( 130 , 155 ), GPC-3 ( 128 ), CD123 ( 131 , 156 ), CD5, CEA, CD20 ( 10 ), B7H3 B7H3 ( 157 ), and PSCA ( 151 ) ( Table 2 ). While CD19-targeting CAR-T products have earned FDA approval for treating B-cell lymphoma and leukemia, they carry risks, like CRS, neurotoxicity, and B-cell aplasia, primarily due to on-target off-tumor toxicities ( 152 , 153 ).…”

Section: Engineering Strategies: the Advances And Advantages Of γδT C...mentioning

confidence: 99%

“…More recently, non-permanent gene transfer methods that utilize non-integrating gene delivery like mRNA-based CAR expression have started to gain traction ( 154 ). The utilization of mRNA in CAR-T cells allows for a “biodegradable” approach, in which the cell’s potency is short-term.…”

Section: Engineering Strategies: the Advances And Advantages Of γδT C...mentioning

confidence: 99%

“…These include EGFR-Vδ2, CD1d-Vδ2, CD40-Vδ2, and PSMA-Vδ2 bsTCEs ( Table 3 ). EGFR-Vδ2 bsTCEs have displayed compelling activation of Vγ9Vδ2 T cells which induce cytotoxicity against EGFR+ tumor cells ( 137 , 154 ). The CD1d-Vδ2 bsTCE, or LAVA-051, has shown anti-tumor potential against hematological malignancies expressing CD1d in preclinical models ( 176 ).…”

Section: Engineering Strategies: the Advances And Advantages Of γδT C...mentioning

confidence: 99%

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Advancements in γδT cell engineering: paving the way for enhanced cancer immunotherapy

Yuan,

Wang,

Hawes

et al. 2024

Front. Immunol.

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Comprising only 1-10% of the circulating T cell population, γδT cells play a pivotal role in cancer immunotherapy due to their unique amalgamation of innate and adaptive immune features. These cells can secrete cytokines, including interferon-γ (IFN-γ) and tumor necrosis factor-α (TNF-α), and can directly eliminate tumor cells through mechanisms like Fas/FasL and antibody-dependent cell-mediated cytotoxicity (ADCC). Unlike conventional αβT cells, γδT cells can target a wide variety of cancer cells independently of major histocompatibility complex (MHC) presentation and function as antigen-presenting cells (APCs). Their ability of recognizing antigens in a non-MHC restricted manner makes them an ideal candidate for allogeneic immunotherapy. Additionally, γδT cells exhibit specific tissue tropism, and rapid responsiveness upon reaching cellular targets, indicating a high level of cellular precision and adaptability. Despite these capabilities, the therapeutic potential of γδT cells has been hindered by some limitations, including their restricted abundance, unsatisfactory expansion, limited persistence, and complex biology and plasticity. To address these issues, gene-engineering strategies like the use of chimeric antigen receptor (CAR) T therapy, T cell receptor (TCR) gene transfer, and the combination with γδT cell engagers are being explored. This review will outline the progress in various engineering strategies, discuss their implications and challenges that lie ahead, and the future directions for engineered γδT cells in both monotherapy and combination immunotherapy.

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The potential of γδ CAR and TRuC T cells: An unearthed treasure

Schamel,

Zintchenko,

Nguyen

et al. 2024

Eur J Immunol

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Recent years have witnessed the success of αβ T cells engineered to express chimeric antigen receptors (CARs) in treating haematological cancers. CARs combine the tumour antigen binding capability of antibodies with the signalling functions of the T‐cell receptor (TCR) ζ chain and co‐stimulatory receptors. Despite the success, αβ CAR T cells face limitations. Possible solutions would be the use of γδ T cells and new chimeric receptors, such as TCR fusion constructs (TRuCs). Notably, γδ CAR T cells are gaining traction in pre‐clinical and clinical studies, demonstrating a promising safety profile in several pilot studies. This review delves into the current understanding of γδ CAR and TCR fusion construct T cells, exploring the opportunities and challenges they present for cancer treatment.

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Enhancing the effectiveness of γδ T cells by mRNA transfection of chimeric antigen receptors or bispecific T cell engagers

Cited by 10 publications

References 61 publications

Directing the migration of serum-free, ex vivo-expanded Vγ9Vδ2 T cells

Directing the migration of serum-free, ex vivo-expanded Vγ9Vδ2 T cells

Advancements in γδT cell engineering: paving the way for enhanced cancer immunotherapy

The potential of γδ CAR and TRuC T cells: An unearthed treasure

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