Development of ICT01, a first-in-class, anti-BTN3A antibody for activating Vγ9Vδ2 T cell–mediated antitumor immune response

Gassart, Aude De; Le, Kieu-Suong; Brune, Patrick; Agaugué, Sophie; Sims, Jennifer S.; Goubard, Armelle; Castellano, Rémy; Joalland, Noémie; Scotet, Emmanuel; Collette, Yves; Valentin, Emmanuel Di; Ghigo, Clément; Pasero, Chris; Colazet, Magali; Guillén, Jaime; Cano, Carla E.; Marabelle, Aurélien; Bonno, Johann De; Hoet, René; Truneh, Alemseged; Olive, Daniel; Frohna, Paul

doi:10.1126/scitranslmed.abj0835

Cited by 77 publications

(65 citation statements)

References 52 publications

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“…However, this approach is not tumor specific as BTN3A is broadly expressed and could also be hampered by soluble BTN3A molecules potentially acting as decoy receptors ( 83 ). In immunodeficient NSG mice, treatment with ICT01 resulted in in vivo activation of adoptively transferred human Vγ9Vδ2 T-cells and delayed outgrowth of the AML cell line MOLM14 ( 84 ). The EVICTION trial is a Phase I/IIa clinical trial currently testing the effect of ICT01 in relapsed/refractory advanced-stage hematologic malignancies as a monotherapy and in a broad range of solid tumors as monotherapy or in combination with pembrolizumab (NCT04243499).…”

Section: Present and Future Studies Involving γδ T-cellsmentioning

confidence: 99%

Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future

et al. 2022

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γδ T-cells directly recognize and kill transformed cells independently of HLA-antigen presentation, which makes them a highly promising effector cell compartment for cancer immunotherapy. Novel γδ T-cell-based immunotherapies, primarily focusing on the two major γδ T-cell subtypes that infiltrate tumors (i.e. Vδ1 and Vδ2), are being developed. The Vδ1 T-cell subset is enriched in tissues and contains both effector T-cells as well as regulatory T-cells with tumor-promoting potential. Vδ2 T-cells, in contrast, are enriched in circulation and consist of a large, relatively homogeneous, pro-inflammatory effector T-cell subset. Healthy individuals typically harbor in the order of 50-500 million Vγ9Vδ2 T-cells in the peripheral blood alone (1-10% of the total CD3+ T-cell population), which can rapidly expand upon stimulation. The Vγ9Vδ2 T-cell receptor senses intracellular phosphorylated metabolites, which accumulate in cancer cells as a result of mevalonate pathway dysregulation or upon pharmaceutical intervention. Early clinical studies investigating the therapeutic potential of Vγ9Vδ2 T-cells were based on either ex vivo expansion and adoptive transfer or their systemic activation with aminobisphosphonates or synthetic phosphoantigens, either alone or combined with low dose IL-2. Immune-related adverse events (irAE) were generally \mild, but the clinical efficacy of these approaches provided overall limited benefit. In recent years, critical advances have renewed the excitement for the potential of Vγ9Vδ2 T-cells in cancer immunotherapy. Here, we review γδ T-cell-based therapeutic strategies and discuss the prospects of those currently evaluated in clinical studies in cancer patients as well as future therapies that might arise from current promising pre-clinical results.

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Section: Present and Future Studies Involving γδ T-cellsmentioning

confidence: 99%

Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future

et al. 2022

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“… 45 Other recent developments to harness γδ T cells for cancer immunotherapy include the design of bi-specific γδ T-cell engagers, the application of agonistic anti-BTN3A1 antibodies for in vivo activation of Vδ2 T cells, or the CAR modification of γδ T cells. 11 , 13 , 46 However, based on experience with other immunotherapies, it is expected that γδ T-cell immunotherapy will require additional strategies to enhance the efficacy and to counteract the immunosuppressive tumor microenvironment. 11 , 14 Along this line, STING ligands have attracted much attention as they have been shown to promote anti-tumor activity at multiple levels, including direct induction of cell death in some tumors, 17 , 23 modulation of tumor cell antigenicity, 24 synergistic action with cytokines, chemotherapeutic drugs and checkpoint inhibitors, 19 , 21 , 25 , 26 and modulation of the tumor microenvironment to enhance CD8 T-cell immunity.…”

Section: Discussionmentioning

confidence: 99%

Stimulatory and inhibitory activity of STING ligands on tumor-reactive human gamma/delta T cells

et al. 2022

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Ligands for Stimulator of Interferon Genes (STING) receptor are under investigation as adjuvants in cancer therapy. Multiple effects have been described, including induction of immunogenic cell death and enhancement of CD8 T-cell mediated anti-tumor immunity. However, the potential effects of STING ligands on activation and effector functions of tumor-reactive human γδ T cells have not yet been investigated. We observed that cyclic dinucleotide as well as novel non-dinucleotide STING ligands diABZI and MSA-2 co-stimulated cytokine induction in Vδ2 T cells within peripheral blood mononuclear cells but simultaneously inhibited their proliferative expansion in response to the aminobisphosphonate Zoledronate and to γδ T-cell specific phosphoantigen. In purified γδ T cells, STING ligands co-stimulated cytokine induction but required the presence of monocytes. STING ligands strongly stimulated IL-1β and TNF-α secretion in monocytes and co-stimulated cytokine induction in short-term expanded Vδ2 γδ T-cell lines. Simultaneously, massive cell death was triggered in both cell populations. Activation of STING as revealed by TBK1/IRF3 phosphorylation and IP-10 secretion varied among STING-expressing tumor cells. STING ligands modulated tumor cell killing by Vδ2 T cells as analyzed in Real-Time Cell Analyzer to variable degree, depending on the tumor target and time course kinetics. Our study reveals complex regulatory effects of STING ligands on human γδ T cells in vitro . These results help to define conditions where STING ligands might boost the efficacy of γδ T cell immunotherapy in vivo .

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“…Interestingly, even in absence of Vγ9Vδ2 T cells, administration of zoledronate had also a beneficial effect ( 37 ) which indicates that (partial) reversal of BTN3A1 immunosuppression might also involve PAgs. Another aspect is the interpretation of an ongoing clinical trial with the agonistic BTN3A specific monoclonal antibody ICT01 (ClinicalTrials.gov-Identifier: NCT04243499) where a positive clinical outcome might not only result from activation of Vγ9Vδ2 T cells ( 38 ) but also by reconstituting a BTN3-suppressed αβ T cell.…”

Section: Other Function Of Butyrophilins and Immune Therapymentioning

confidence: 99%

Butyrophilins: γδ T Cell Receptor Ligands, Immunomodulators and More

Herrmann

Karunakaran

2022

Front. Immunol.

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Butyrophilins (BTN) are relatives of the B7 family (e.g., CD80, PD-L1). They fulfill a wide range of functions including immunomodulation and bind to various receptors such as the γδ T cell receptor (γδTCR) and small molecules. One intensively studied molecule is BTN3A1, which binds via its cytoplasmic B30.2 domain, metabolites of isoprenoid synthesis, designated as phosphoantigen (PAg), The enrichment of PAgs in tumors or infected cells is sensed by Vγ9Vδ2 T cells, leading to the proliferation and execution of effector functions to remove these cells. This article discusses the contribution of BTNs, the related BTNL molecules and SKINT1 to the development, activation, and homeostasis of γδ T cells and their immunomodulatory potential, which makes them interesting targets for therapeutic intervention.

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Development of ICT01, a first-in-class, anti-BTN3A antibody for activating Vγ9Vδ2 T cell–mediated antitumor immune response

Abstract: ICT01, a humanized BTN3A mAb, activates Vγ9Vδ2 T cell antitumor immunity and is well tolerated and pharmacodynamically active in patients.

Cited by 77 publications

References 52 publications

Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future

Gamma Delta T-Cell Based Cancer Immunotherapy: Past-Present-Future

Stimulatory and inhibitory activity of STING ligands on tumor-reactive human gamma/delta T cells

Butyrophilins: γδ T Cell Receptor Ligands, Immunomodulators and More

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