A Bispecific Single-Domain Antibody Boosts Autologous Vγ9Vδ2-T Cell Responses Toward CD1d in Chronic Lymphocytic Leukemia

Weerdt, Iris de; Lameris, Roeland; Ruben, Jurjen M.; Boer, Renate de; Kloosterman, Jan; King, Lisa A.; Levin, Mark‐David; Parren, Paul W.H.I.; Gruijl, Tanja D. de; Kater, Arnon P.; Vliet, Hans J. van der

doi:10.1158/1078-0432.ccr-20-4576

Cited by 34 publications

(25 citation statements)

References 67 publications

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“…Given this, the potential engagement of therapeutic Abs with the product of Vg9Vd2 cells can provide an efficient alternative against LCs (223). Several studies have shown that gd T cells mediate leukemic regression via a CD16dependent pathway (136,(223)(224)(225)(226), in particular the Vg9Vd2 subtype, which positively regulates CD16 and TNF expression when stimulated with pAgs (227).…”

Section: Antibodies Direct Gd T Cells Against Lcsmentioning

confidence: 99%

“…Finally, it has been shown that CD1d is also an attractive target. A recent study showed that CD1d specific single domain Abs can guide γδ T cells ( 226 ). These engagers were able to mobilize and activate these lymphocytes against autologous LCs from patients with CLL.…”

Section: Harnessing γδ T Cells Against Leukemia: From Marrow To Bloodmentioning

confidence: 99%

“…These engagers were able to mobilize and activate these lymphocytes against autologous LCs from patients with CLL. This allowed γδ T cells to produce many inflammatory molecules and maintain their pAgs reactivity ( 226 ). Taken together, the many studies reviewed here allow us to suggest that the therapeutic application of Abs can be improved with the use of N-BPs that enhance γδ T cell activation.…”

Section: Harnessing γδ T Cells Against Leukemia: From Marrow To Bloodmentioning

confidence: 99%

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γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

et al. 2021

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Recently, many discoveries have elucidated the cellular and molecular diversity in the leukemic microenvironment and improved our knowledge regarding their complex nature. This has allowed the development of new therapeutic strategies against leukemia. Advances in biotechnology and the current understanding of T cell-engineering have led to new approaches in this fight, thus improving cell-mediated immune response against cancer. However, most of the investigations focus only on conventional cytotoxic cells, while ignoring the potential of unconventional T cells that until now have been little studied. γδ T cells are a unique lymphocyte subpopulation that has an extensive repertoire of tumor sensing and may have new immunotherapeutic applications in a wide range of tumors. The ability to respond regardless of human leukocyte antigen (HLA) expression, the secretion of antitumor mediators and high functional plasticity are hallmarks of γδ T cells, and are ones that make them a promising alternative in the field of cell therapy. Despite this situation, in particular cases, the leukemic microenvironment can adopt strategies to circumvent the antitumor response of these lymphocytes, causing their exhaustion or polarization to a tumor-promoting phenotype. Intervening in this crosstalk can improve their capabilities and clinical applications and can make them key components in new therapeutic antileukemic approaches. In this review, we highlight several characteristics of γδ T cells and their interactions in leukemia. Furthermore, we explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of γδ T cells against the tumor. Finally, we outline our perspectives on their therapeutic applicability and indicate outstanding issues for future basic and clinical leukemia research, in the hope of contributing to the advancement of studies on γδ T cells in cancer immunotherapy.

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Section: Antibodies Direct Gd T Cells Against Lcsmentioning

confidence: 99%

Section: Harnessing γδ T Cells Against Leukemia: From Marrow To Bloodmentioning

confidence: 99%

Section: Harnessing γδ T Cells Against Leukemia: From Marrow To Bloodmentioning

confidence: 99%

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γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

et al. 2021

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“…Moreover, Vγ9Vδ2-T cells have become a novel potential immunotherapeutic for Chronic Lymphocytic Leukemia (CLL) due to their capacity to be triggered by phosphoantigens which are overproduced by CLL. A nanobody-based CD1d-specific Vγ9Vδ2-T cell engager was generated to induce robust activation and degranulation of Vg9Vd2-T cells and consequent lysis of autologous leukemic cells ( 29 ).…”

Section: Nanobody Applications In Cancer Researchmentioning

confidence: 99%

Research Progress and Applications of Multivalent, Multispecific and Modified Nanobodies for Disease Treatment

et al. 2022

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Recombinant antibodies such as nanobodies are progressively demonstrating to be a valid alternative to conventional monoclonal antibodies also for clinical applications. Furthermore, they do not solely represent a substitute for monoclonal antibodies but their unique features allow expanding the applications of biotherapeutics and changes the pattern of disease treatment. Nanobodies possess the double advantage of being small and simple to engineer. This combination has promoted extremely diversified approaches to design nanobody-based constructs suitable for particular applications. Both the format geometry possibilities and the functionalization strategies have been widely explored to provide macromolecules with better efficacy with respect to single nanobodies or their combination. Nanobody multimers and nanobody-derived reagents were developed to image and contrast several cancer diseases and have shown their effectiveness in animal models. Their capacity to block more independent signaling pathways simultaneously is considered a critical advantage to avoid tumor resistance, whereas the mass of these multimeric compounds still remains significantly smaller than that of an IgG, enabling deeper penetration in solid tumors. When applied to CAR-T cell therapy, nanobodies can effectively improve the specificity by targeting multiple epitopes and consequently reduce the side effects. This represents a great potential in treating malignant lymphomas, acute myeloid leukemia, acute lymphoblastic leukemia, multiple myeloma and solid tumors. Apart from cancer treatment, multispecific drugs and imaging reagents built with nanobody blocks have demonstrated their value also for detecting and tackling neurodegenerative, autoimmune, metabolic, and infectious diseases and as antidotes for toxins. In particular, multi-paratopic nanobody-based constructs have been developed recently as drugs for passive immunization against SARS-CoV-2 with the goal of impairing variant survival due to resistance to antibodies targeting single epitopes. Given the enormous research activity in the field, it can be expected that more and more multimeric nanobody molecules will undergo late clinical trials in the next future.Systematic Review Registration

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“…In the preclinical setting, a CD40 bispecific γδ T-cell engager has shown to induce a powerful Vγ9Vδ2 T cell-dependent anti-leukemic response, also preventing CD40/CD40L-induced pro-survival signaling ( 68 ). More recently, a CD1d-specific Vγ9Vδ2-T cell engager based on single-domain antibodies has been explored in preclinical CLL models, showing its capability of determining cytokine production and degranulation by Vγ9Vδ2-T cells from both CLL patients and controls, and of inducing CD1d-dependent tumor lysis ( 69 ). Consistently with previous studies ( 70 ), the addition of ATRA increased CD1d expression and potentiated Vγ9Vδ2 T-cell engager-induced cytotoxicity of CLL cells ( 69 ).…”

Section: Successful Immunotherapy Options In Cllmentioning

confidence: 99%

Immunotherapeutic Strategies in Chronic Lymphocytic Leukemia: Advances and Challenges

et al. 2022

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Immune-based therapeutic strategies have drastically changed the landscape of hematological disorders, as they have introduced the concept of boosting immune responses against tumor cells. Anti-CD20 monoclonal antibodies have been the first form of immunotherapy successfully applied in the treatment of CLL, in the context of chemoimmunotherapy regimens. Since then, several immunotherapeutic approaches have been studied in CLL settings, with the aim of exploiting or eliciting anti-tumor immune responses against leukemia cells. Unfortunately, despite initial promising data, results from pilot clinical studies have not shown optimal results in terms of disease control - especially when immunotherapy was used individually - largely due to CLL-related immune dysfunctions hampering the achievement of effective anti-tumor responses. The growing understanding of the complex interactions between immune cells and the tumor cells has paved the way for the development of new combined approaches that rely on the synergism between novel agents and immunotherapy. In this review, we provide an overview of the most successful and promising immunotherapeutic modalities in CLL, including both antibody-based therapy (i.e. monoclonal antibodies, bispecific antibodies, bi- or tri- specific killer engagers) and adoptive cellular therapy (i.e. CAR T cells and NK cells). We also provide examples of successful new combination strategies and some insights on future perspectives.

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A Bispecific Single-Domain Antibody Boosts Autologous Vγ9Vδ2-T Cell Responses Toward CD1d in Chronic Lymphocytic Leukemia

Cited by 34 publications

References 67 publications

γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

Research Progress and Applications of Multivalent, Multispecific and Modified Nanobodies for Disease Treatment

Immunotherapeutic Strategies in Chronic Lymphocytic Leukemia: Advances and Challenges

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