Phosphostim-Activated T Cells Kill Autologous Metastatic Renal Cell Carcinoma

Institut National de la Santé et de la Recherche Médicale Unité 487, Institut Fédératif de Recherche 54, Institut Gustave Roussy, Villejuif, France.
The Journal of Immunology (Impact Factor: 4.92). 03/2005; 174(3):1338-47. DOI: 10.4049/jimmunol.174.3.1338
Source: PubMed


Metastatic renal cell carcinoma, inherently resistant to conventional treatments, is considered immunogenic. Indeed, partial responses are obtained after treatment with cytokines such as IL-2 or IFN-alpha, suggesting that the immune system may control the tumor growth. In this study, we have investigated the ability of the main subset of peripheral gammadelta lymphocytes, the Vgamma9Vdelta2-TCR T lymphocytes, to induce an effective cytotoxic response against autologous primary renal cell carcinoma lines. These gammadelta T cells were expanded ex vivo using a Vgamma9Vdelta2 agonist, a synthetic phosphoantigen called Phosphostim. From 11 of 15 patients, the peripheral Vgamma9Vdelta2 T cells were amplified in vitro by stimulating PBMCs with IL-2 and Phosphostim molecule. These expanded Vgamma9Vdelta2 T cells express activation markers and exhibit an effector/memory phenotype. They display a selective lytic potential toward autologous primary renal tumor cells and not against renal NC. The lytic activity involves the perforin-granzyme pathway and is mainly TCR and NKG2D receptor dependent. Furthermore, an increased expression of MHC class I-related molecule A or B proteins, known ligands of NKG2D, are detected on primary renal tumor cells. Interestingly, from 2 of the 11 positive cultures in response to Phosphostim, expanded-Vgamma9Vdelta2 T cells present an expression of killer cell Ig-like receptors, suggesting their prior recruitment in vivo. Unexpectedly, on serial frozen sections from three tumors, we observe a gammadelta lymphocyte infiltrate that was mainly composed of Vgamma9Vdelta2 T cells. These results outline that Vgamma9Vdelta2-TCR effectors may represent a promising approach for the treatment of metastatic renal cell carcinoma.

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    • "Mice deficient in γδ T cells show a significantly increased incidence of tumors and provide clear evidence for an immune surveillance function of these unconventional lymphocytes [8]. Human Vγ9Vδ2 T cells can kill a broad spectrum of tumor cells with or without reduced MHC class I molecules expression in an MHC-unrestricted manner [9–14]. Moreover, γδ T cells can migrate as infiltrating lymphocytes into solid tumors [9] and can recognize and eliminate cultured malignant cells (primary cells or cell lines) from myeloma [10, 11], non-Hodgkin lymphoma [12], prostate cancer [13], renal cell carcinoma [14], colon carcinoma [15], and squamous cell carcinoma [16]. "
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    ABSTRACT: Restricted T-cell receptor (TCR) Vα/Vβ repertoire expression and clonal expansion of αβ T cells especially for putative tumor-associated antigens were observed in patients with hematological malignancies. To further characterize the γδ T-cell immune status in B-cell non-Hodgkin lymphoma (B-NHL), we investigated the distribution and clonality of TCR Vγ/Vδ repertoire in peripheral blood (PB), bone marrow (BM), and lymph node (LN) from patients with B-NHL. Four newly diagnosed B-NHL cases, including three with diffuse large B-cell lymphoma (DLBCL) and one with small lymphocytic lymphoma (SLL), were enrolled. The restrictive expression of TCR Vγ/Vδ subfamilies with different distribution patterns could be detected in PB, BM, or LN from all of four patients, and partial subfamily T cells showed clonal proliferation. At least one clonally expanded Vδ subfamily member was found in PB from each patient. However, the expression pattern and clonality of TCR Vγ/Vδ changed in different immune organs and showed individual feature in different patients. The clonally expanded Vδ5, Vδ6, and Vδ8 were detected only in PB but neither in BM nor LN while clonally expanded Vδ2 and Vδ3 could be detected in both PB and BM/LN. In conclusion, the results provide a preliminary profile of distribution and clonality of TCR γ/δ subfamilies T cells in PB, BM, and LN from B-NHL; similar clonally expanded Vδ subfamily T cells in PB and BM may be related to the same B-cell lymphoma-associated antigens, while the different reactive clonally expanded Vγ/Vδ T cells may be due to local immune response.
    Research Journal of Immunology 05/2014; 2014:241246. DOI:10.1155/2014/241246
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    • "Beside their known anti-infectious activity -in particular following allogeneic HSCT- it was shown that GDT cells are able to kill a wide variety of tumour cell lines from very diverse origins [28]. GDT cells can be selectively expanded in vivo or in vitro in the presence of aminobisphosphonates without prior antigen priming [29]. Recently, it has been shown that human GDT cells can be expanded in the presence of zoledronate and efficiently transduced with a retroviral vector encoding a CD19-specific CAR. "
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    ABSTRACT: Leukaemia immunotherapy represents a fascinating and promising field of translational research, particularly as an integrative approach of bone marrow transplantation. Adoptive immunotherapy by the use of donor-derived expanded leukaemia-specific T cells has showed some kind of clinical response, but the major advance is nowadays represented by gene manipulation of donor immune cells, so that they acquire strict specificity towards the tumour target and potent lytic activity, followed by significant proliferation, increased survival and possibly anti-tumour memory state. This is achieved by gene insertion of Chimeric T-cell Antigen Receptors (CARs), which are artificial molecules containing antibody-derived fragments (to bind the specific target), joined with potent signalling T-Cell Receptor (TCR)-derived domains that activate the manipulated cells. This review will discuss the main application of this approach particularly focusing on the paediatric setting, raising advantages and disadvantages and discussing relevant perspectives of use in the nearest future.
    Italian Journal of Pediatrics 09/2011; 37(1):46. DOI:10.1186/1824-7288-37-46 · 1.52 Impact Factor
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    • "Although healthy donor Vg9Vd2 T cells expand massively when stimulated in vitro by IL-2 in combination with phosphoantigens or bisphosphonates (Wilhelm et al, 2003), the in vitro proliferative capacity of Vg9Vd2 T cells from patients with malignancy seems less reproducible. For example, in vitro expansion of Vg9Vd2 T cells was poor in 50% of lymphoma patients (Wilhelm et al, 2003) and in 25% of renal carcinoma patients (Viey et al, 2005). It is unknown whether this defect in Vg9Vd2 T cell proliferation is tumour specific or broadly associated with malignancy, and it is also unknown whether the differences are directly related to differences in Vg9Vd2 T cells or due to other cellular constituents in the expansion cultures evaluated. "
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    ABSTRACT: Adoptive transfer of ex vivo expanded autologous Vγ9Vδ2 T cells may be of therapeutic benefit for cancer because of their potent direct cytotoxicity towards tumour cells, synergistic cytotoxicity when combined with aminobisphosphonates and enhancement of antibody-dependent cell-mediated cytotoxicity. To determine the feasibility and clinical safety of therapy with ex vivo expanded, activated Vγ9Vδ2 T cells in combination with zoledronate, we enrolled 18 subjects with advanced solid tumours into a phase I clinical study. Administered indium(111)-oxine-labelled Vγ9Vδ2 T cells were tracked in a cohort of patients. Administered Vγ9Vδ2 T cells had an activated effector memory phenotype, expressed chemokine receptors predictive of homing to peripheral tissues and were cytotoxic in vitro against tumour targets. Adoptively transferred Vγ9Vδ2 T cells trafficked predominantly to the lungs, liver and spleen and, in some patients, to metastatic tumour sites outside these organs. No dose-limiting toxicity was observed, but most patients progressed on study therapy. However, three patients administered Vγ9Vδ2 T cells while continuing previously ineffective therapy had disease responses, suggesting an additive effect. Therapy with aminobisphosphonate-activated Vγ9Vδ2 T cells is feasible and well tolerated, but therapeutic benefits appear only likely when used in combination with other therapies.
    British Journal of Cancer 08/2011; 105(6):778-86. DOI:10.1038/bjc.2011.293 · 4.84 Impact Factor
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