γδ T Lymphocytes Count Is Normal and Expandable in Peripheral Blood of Patients with Follicular Lymphoma, Whereas It Is Decreased in Tumor Lymph Nodes Compared with Inflammatory Lymph Nodes

Braza, Mounia S.; Caraux, Anouk; Rousset, Thérèse; Micheaux, Sylvie Lafaye de; Sicard, Hélène; Squiban, Patrick; Costes, Valérie; Klein, Bernard; Rossi, Jean‐François

doi:10.4049/jimmunol.0901980

Cited by 19 publications

(19 citation statements)

References 44 publications

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“…Along this line, several studies have shown the increase of lytic activity by gd T cells combined with mAbs such as rituximab and TTZ in vitro (25,43). In addition, clinical processes to amplify peripheral gd T cells from cancer patients have been set up by several independent clinical laboratories (44)(45)(46), demonstrating the feasibility of gd T cell-based cancer immunotherapies.…”

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confidence: 97%

Stimulated γδ T Cells Increase the In Vivo Efficacy of Trastuzumab in HER-2+ Breast Cancer

Capietto

Martinet

Fournié

2011

The Journal of Immunology

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One fourth of women with HER-2+ metastatic breast carcinoma are treated with a combination regimen with trastuzumab, but the frequent resistance to this Ab requires definition of new means to improve its bioactivity. The mechanisms of action of trastuzumab involve several pathways including Ab-dependent cellular cytotoxicity. Because human γδ T lymphocytes mediate Ab-dependent cellular cytotoxicity and can be activated further by phosphoantigens, these cells are prone to improve the efficacy of Abs, as recently demonstrated for CD20+ B cell lymphomas. Whether this concept applies as well with carcinomas remained to be demonstrated in vivo, however. In this study, we asked whether a combination of trastuzumab and phosphoantigen-stimulated γδ lymphocytes increases the efficacy of trastuzumab against HER-2+ breast carcinoma cell lines in vivo. We report that repeated infusions of this combination had a better efficacy than that of trastuzumab alone against HER-2+ mammary carcinoma xenografts in mice. In these models, reduction of tumor growth was observed together with trastuzumab opsonization of HER-2+ cells and tumor infiltration by γδ lymphocytes. In addition in humans, the mammary carcinomas of 27 of 30 patients showed significant γδ T cell infiltrates. Altogether, these findings indicate that combination of trastuzumab and stimulated γδ cells represents a new strategy to improve the efficacy of Herceptin (trastuzumab) in HER-2+ breast cancer.

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confidence: 97%

Stimulated γδ T Cells Increase the In Vivo Efficacy of Trastuzumab in HER-2+ Breast Cancer

Capietto

Martinet

Fournié

2011

The Journal of Immunology

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“…First, treatment with BrHPP and IL-2 increases the counts of circulating γδ T-lymphocytes 50-to 100-fold, dramatically expanding the reservoir of these effector cells. 42 Secondly, phosphoantigens may drive γδ T-cell maturation from naïve to effector memory cells, some of which express membrane CD16. 43,44 CD16 + effector memory γδ T cells are more efficient than CD16-γδ T cells at binding and killing CD20…”

Section: Cd8mentioning

confidence: 99%

T-cell killing of primary follicular lymphoma cells is dramatically potentiated by GA101, a type II glycoengineered anti-CD20 monoclonal antibody

Braza¹,

Klein²,

Fiol³

et al. 2010

Haematologica

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BackgroundAnti-CD20 monoclonal antibodies are major therapeutic agents for patients with follicular lymphoma and work through complement-mediated cytotoxicity and antibody-dependent cellular cytotoxicity. Optimization of antibody-dependent cellular cytotoxicity, in particular by amplifying its effectors, could further increase the efficacy of anti-CD20 monoclonal antibodies. Design and MethodsWe investigated the cytotoxic activity of Vγ9Vδ2 T cells against follicular lymphoma cells and whether this killing could be increased by promoting antibody-dependent cellular cytotoxicity with anti-CD20 monoclonal antibodies, in particular a type-II glycoengineered anti-CD20. Vγ9Vδ2 T cells were expanded in vitro in the presence of bromohydrin pyrophosphate (Phosphostim) and interleukin-2 and their ability to kill follicular lymphoma primary cells or cell lines was evaluated by flow cytometry cytotoxic T-lymphocyte assays in the presence or absence of three anti-CD20 monoclonal antibodies: the afucosylated GA101, the chimeric rituximab or the humanized ofatumumab. The ability of these cells to release perforin/granzyme and secrete interferon-γ when co-cultured with follicular lymphoma primary cells or cell lines in the presence or not of the three anti-CD20 monoclonal antibodies was also evaluated by CD107a staining and Elispot assays. ResultsPhosphostim and interleukin-2 expanded Vγ9Vδ2 T cells were cytotoxic to primary follicular lymphoma cells and their cytotoxic potential was dramatically increased by GA101, a type II glycoengineered anti-CD20 monoclonal antibody, and to a lesser extent, by rituximab and ofatumumab. The increased cytotoxicity was associated with increased secretion of perforin/granzyme and interferon-γ. ConclusionsIn-vitro expanded Vγ9Vδ2 T cells efficiently kill primary follicular lymphoma cells and express CD16; anti-CD20 monoclonal antibodies, in particular GA101, dramatically increase the cytotoxic activity of expanded Vγ9Vδ2 T cells. These preclinical results prompt the development of clinical trials using this antibody dependent cellular cytotoxicity property of Vγ9Vδ2 T cells and anti-CD20 monoclonal antibodies.Key words: γδ T-Lymphocytes, follicular lymphoma, anti-CD20 monoclonal antibody, rituximab, ofatumumab. GA101, a type II glycoengineered anti-CD20 monoclonal antibody. Haematologica 2011;96(3):400-407. doi:10.3324/haematol.2010 γδ T-cell killing of primary follicular lymphoma cells is dramatically potentiated by GA101, a type II glycoengineered anti-CD20 monoclonal antibody Citation: Braza MS, Klein B, Fiol G, and Rossi J-F,. γδ T-cell killing of primary follicular lymphoma cells is dramatically potentiated by

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“…For instance, decreased T-cell count has been previously reported in some [90][91][92][93][94][95], but not other [83,96], malignancies particularly in patients with advanced cancer or at a terminal stage, and it has generally been associated with activation-induced cell death (AICD) resulting from T-cell-tumor contact, and is principally due to selective depletion of the V 9V 2 population. Moreover, other factors as, tumor-derived cytokines, chemotherapy and the general health conditions of the patients may all contribute to a global decrease in circulating V 9V 2 Tcells.…”

Section: Limits Tomentioning

confidence: 99%

Optimizing Tumor-Reactive γδT Cells for Antibody-Based Cancer Immunotherapy

Meraviglia¹,

Caccamo²,

Guggino³

et al. 2010

CMM

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Monoclonal antibodies (mAbs) constitute the most rapidly growing class of human therapeutics and the second largest class of drugs after vaccines. The treatment of B-cell malignancies and HER2/Neu(+) breast cancer has benefited considerably from the use of therapeutic mAbs, either alone or in combination with standard chemotherapy. Frequent relapses, however, demonstrate that the bioactivity of these mAbs is still suboptimal. The concept of improving the anti-tumor activity of mAbs is well established and potentiating the cytotoxicity induced by anticancer mAbs can be achieved by strategies that target the downstream cytolytic effector cells. The recruitment of Fcγ receptor-dependent functions appears well suited in this regard, because several lines of evidence suggest that enhancing antibody-dependent cellular cytotoxicity (ADCC) induced by therapeutic mAbs may directly improve their clinical efficacy. The cytolytic effector cells involved in ADCC are FcγR-expressing natural killer (NK) cells, but also γδ T cells can be amplified and finetuned for stronger ADCC activity. γδ T cells are raising a considerable interest in the immunotherapy community given their intrinsic antitumor activity that can be boosted by stimulation with synthetic phosphoantigens (PAgs), or with drugs that cause their accumulation into target cells, like aminobisphosphonates (N-BPs), and low doses interleukin (IL)-2. The field is interesting, and several papers have already explored this approach in solid and haematological malignancies. Thus, we propose that enhancing the efficacy of mAbs by combination with γδ T cell activation may have considerable therapeutic potential for a variety of malignancies, most especially for patients whose FcγR alleles impair ADCC.

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γδ T Lymphocytes Count Is Normal and Expandable in Peripheral Blood of Patients with Follicular Lymphoma, Whereas It Is Decreased in Tumor Lymph Nodes Compared with Inflammatory Lymph Nodes

Cited by 19 publications

References 44 publications

Stimulated γδ T Cells Increase the In Vivo Efficacy of Trastuzumab in HER-2+ Breast Cancer

Stimulated γδ T Cells Increase the In Vivo Efficacy of Trastuzumab in HER-2+ Breast Cancer

T-cell killing of primary follicular lymphoma cells is dramatically potentiated by GA101, a type II glycoengineered anti-CD20 monoclonal antibody

Optimizing Tumor-Reactive γδT Cells for Antibody-Based Cancer Immunotherapy

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γδ T Lymphocytes Count Is Normal and Expandable in Peripheral Blood of Patients with Follicular Lymphoma, Whereas It Is Decreased in Tumor Lymph Nodes Compared with Inflammatory Lymph Nodes

Cited by 19 publications

References 44 publications

Stimulated γδ T Cells Increase the In Vivo Efficacy of Trastuzumab in HER-2+ Breast Cancer

Stimulated γδ T Cells Increase the In Vivo Efficacy of Trastuzumab in HER-2+ Breast Cancer

T-cell killing of primary follicular lymphoma cells is dramatically potentiated by GA101, a type II glycoengineered anti-CD20 monoclonal antibody

Optimizing Tumor-Reactive &#947;&#948;T Cells for Antibody-Based Cancer Immunotherapy

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Optimizing Tumor-Reactive γδT Cells for Antibody-Based Cancer Immunotherapy