IPH1101, the First Specific γδ T Cell Agonist, Shows Potent Immuno-Biological Efficacy in Low Grade Follicular Lymphoma Patients When Combined with Rituximab: Results From a Phase II Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 583-583 ◽  
Author(s):  
Claire Lucas ◽  
Sophie Ingoure ◽  
Elodie Soule ◽  
Bruna Faria ◽  
Fabien Audibert ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase Ii ◽  
Mononuclear Cells ◽  
Phase Ii Study ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Low Grade ◽  
Γδ T Cell ◽  
Blood Samples

Abstract Abstract 583 Background: Non-conventional γδ T lymphocytes have strong anti-tumoral activity, particularly against malignant B cells. IPH1101 is an agonist of γδ T cells, which in the presence of low doses of IL-2 potentiates their direct cytotoxic activity. ADCC is a major molecular mechanism underlying rituximab efficacy. Increasing the number and the activation state of killer lymphocytes mediating ADCC is therefore believed to be beneficial for therapeutic potency. Since γδ T cells have been found capable of mediating ADCC, modulating γδ T cells in the context of rituximab is worth being tested in a clinical trial. The main purpose was to assess the clinical efficacy of IPH1101 combined with rituximab in FL patients (see abstract by Laurent et al for clinical data) and the pharmacological activity of IPH1101 in this trial was also closely monitored. Material and methods: Blood samples were collected weekly in this Phase II study patients who were treated with the combination of rituximab (375 mg/m2), IPH1101 (750 mg/m2, 3 times every 3 weeks) and IL-2 (8 MIU daily s.c. for 5 days). Fresh whole blood samples were extensively analysed by flow cytometry for the follow-up of immune cell changes, such as differentiation, activation of proliferation. Plasma samples were collected within hours after each IPH1101 injection to monitor cytokine release. Blood samples were also drawn pre-dose and at Day 8 of each IPH1101 injection to prepare mononuclear cells and assess them for functional activity ex vivo in various standardized assays. Results: In FL patients treated with rituximab, IPH1101 combined with low dose IL-2 induced robust and sustained γδ T cell differentiation and amplification in blood. In parallel, NK and regulatory T (Treg) cells also proliferated in response to IL-2, though to a much lesser extent. The ratio between effector and suppressor cells remained highly favourable throughout the study. In some patients, γδ T cells showed an increased expression of surface FcRγIIIa, the receptor for rituximab. Pro-inflammatory cytokines were released immediately after each injection, with expected profile and kinetics. Finally, ex vivo functionality assays (direct cytoxicity and CD107a induction) showed an improved overall ADCC-mediated cytotoxic potential of blood cells induced by the treatment. Conclusion: Altogether, these data demonstrate that effector γδ T cells can be specifically activated and expanded in FL patients receiving standard rituximab therapy through the use of their dedicated agonist IPH1101. The direct immune manipulation of this lymphocyte subset in vivo translates into potentiated anti-lymphoma activity attested by several pharmaco-dynamic parameters. Disclosures: Lucas: Innate Pharma: Employment. Ingoure:Innate Pharma: Employment. Soule:Innate Pharma: Employment. Faria:Innate Pharma: Employment. Audibert:Innate Pharma: Employment. Blery:Innate Pharma: Employment. Beautier:Innate Pharma: Employment. Romagne:Innate Pharma: Employment. de Micheaux:Innate Pharma: Employment.

γδ T cells for immune therapy of patients with lymphoid malignancies

Blood ◽  
2003 ◽  
Vol 102 (1) ◽  
pp. 200-206 ◽  
Author(s):  
Martin Wilhelm ◽  
Volker Kunzmann ◽  
Susanne Eckstein ◽  
Peter Reimer ◽  
Florian Weissinger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Low Dose ◽  
Γδ T Cells ◽  
Low Grade ◽  
Treatment Schedule ◽  
Γδ T Cell

Abstract There is increasing evidence that γδ T cells have potent innate antitumor activity. We described previously that synthetic aminobisphosphonates are potent γδ T cell stimulatory compounds that induce cytokine secretion (ie, interferon γ [IFN-γ]) and cell-mediated cytotoxicity against lymphoma and myeloma cell lines in vitro. To evaluate the antitumor activity of γδ T cells in vivo, we initiated a pilot study of low-dose interleukin 2 (IL-2) in combination with pamidronate in 19 patients with relapsed/refractory low-grade non-Hodgkin lymphoma (NHL) or multiple myeloma (MM). The objectives of this trial were to determine toxicity, the most effective dose for in vivo activation/proliferation of γδ T cells, and antilymphoma efficacy of the combination of pamidronate and IL-2. The first 10 patients (cohort A) who entered the study received 90 mg pamidronate intravenously on day 1 followed by increasing dose levels of continuous 24-hour intravenous (IV) infusions of IL-2 (0.25 to 3 × 106 IU/m2) from day 3 to day 8. Even at the highest IL-2 dose level in vivo, γδ T-cell activation/proliferation and response to treatment were disappointing with only 1 patient achieving stable disease. Therefore, the next 9 patients were selected by positive in vitro proliferation of γδ T cells in response to pamidronate/IL-2 and received a modified treatment schedule (6-hour bolus IV IL-2 infusions from day 1-6). In this patient group (cohort B), significant in vivo activation/proliferation of γδ T cells was observed in 5 patients (55%), and objective responses (PR) were achieved in 3 patients (33%). Only patients with significant in vivo proliferation of γδ T cells responded to treatment, indicating that γδ T cells might contribute to this antilymphoma effect. Overall, administration of pamidronate and low-dose IL-2 was well tolerated. In conclusion, this clinical trial demonstrates, for the first time, that γδ T-cell–mediated immunotherapy is feasible and can induce objective tumor responses. (Blood. 2003;102:200-206)

scholarly journals Activation-induced Modification in the CD3 Complex of the γδ T Cell Receptor

2002 ◽  
Vol 196 (10) ◽  
pp. 1355-1361 ◽  
Author(s):  
Sandra M. Hayes ◽  
Karen Laky ◽  
Dalal El-Khoury ◽  
Dietmar J. Kappes ◽  
B.J. Fowlkes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Intraepithelial Lymphocytes ◽  
Subunit Composition ◽  
Γδ T Cell ◽  
Receptor Complexes ◽  
Functional Consequences

The T cell antigen receptor complexes expressed on αβ and γδ T cells differ not only in their respective clonotypic heterodimers but also in the subunit composition of their CD3 complexes. The γδ T cell receptors (TCRs) expressed on ex vivo γδ T cells lack CD3δ, whereas αβ TCRs contain CD3δ. While this result correlates with the phenotype of CD3δ−/− mice, in which γδ T cell development is unaffected, it is inconsistent with the results of previous studies reporting that CD3δ is a component of the γδ TCR. Since earlier studies examined the subunit composition of γδ TCRs expressed on activated and expanded peripheral γδ T cells or γδ TCR+ intestinal intraepithelial lymphocytes, we hypothesized that activation and expansion may lead to changes in the CD3 subunit composition of the γδ TCR. Here, we report that activation and expansion do in fact result in the inclusion of a protein, comparable in mass and mobility to CD3δ, in the γδ TCR. Further analyses revealed that this protein is not CD3δ, but instead is a differentially glycosylated form of CD3γ. These results provide further evidence for a major difference in the subunit composition of αβ- and γδ TCR complexes and raise the possibility that modification of CD3γ may have important functional consequences in activated γδ T cells.

scholarly journals Zoledronic Acid Boosts γδ T-Cell Activity in Children Receiving αβ+ T and CD19+ CELL-Depleted Grafts from a Haplo-Identical DONOR

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5771-5771
Author(s):  
Giulia Barbarito ◽  
Irma Airoldi ◽  
Alessia Zorzoli ◽  
Alice Bertaina ◽  
Andrea Petretto ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Zoledronic Acid ◽  
Conflicts Of Interest ◽  
High Resolution Mass Spectrometry ◽  
Ex Vivo ◽  
Cell Activity ◽  
Γδ T Cells ◽  
Leukemia Cells ◽  
Γδ T Cell

Abstract A new method of graft manipulation based on physical removal of αβ+ T cells and CD19+ B cells, leaving mature NK cells and γδ T cells in the graft, has been recently developed for HLA-haploidentical HSCT. We demonstrated that γδ T cells collected from transplanted patients are endowed with capacity of killing leukemia cells after ex vivo treatment with zoledronic acid (ZOL). Thus, we hypothesized that infusion of ZOL in patients receiving this type of graft, may boost γδ T cell cytotoxic activity against leukemia cells. Thirty-three patients were treated with ZOL every 28 days at least twice. γδ T cells before and after ZOL treatments were studied till at least 7 months after HSCT by high-resolution mass spectrometry, flow-cytometry, and degranulation assay. Proteomic analysis of γd T cells purified from patients showed that, starting from the first infusion, ZOL caused up-regulation of proteins involved in activation processes and immune response, paralleled by down-regulation of proteins involved in proliferation. These findings are consistent with an induction of Vδ2 cell differentiation, paralleled by increased cytotoxicity of both Vδ1 and Vδ2 cells against primary leukemia blasts. Furthermore, a proteomic signature was identified for each individual ZOL treatment. Patients given 3 or more ZOL infusions had a better probability of survival in comparison to those given 1 or 2 treatments. In conclusion,ZOL influences Vδ2 cell activity, determines a specific proteomic signature and enhances anti-leukemia activity, this potentially resulting into an increased anti-tumor effect. Disclosures No relevant conflicts of interest to declare.

Cognitive Study of Reactivity to IPH1101 of Peripheral γδ T Lymphocytes from Chronic Myeloid Leukemia, Multiple Myeloma and Follicular Lymphoma Patients.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1530-1530
Author(s):  
Helene Sicard ◽  
Jean-Francois Rossi ◽  
Philippe Rousselot ◽  
Alexis Collette ◽  
Christine Paiva ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
Ex Vivo ◽  
Γδ T Cells ◽  
Small Sample ◽  
Proliferative Capacity ◽  
Γδ T Cell ◽  
Specific Stimulus

Abstract Background: IPH1101, a chemically-synthesized, structural analogue of γδ T lymphocyte natural phosphoantigens, combined with low doses of IL-2 induces a highly selective proliferation of γδ T cells, non conventional lymphocytes bearing potent effector and regulatory immune functions. Today, IPH1101 is tested in Phase II clinical trials in different indications and settings (alone or in combination), as the first specific γδ T cell-mediated immunotherapy. Whereas γδT cells from healthy donors always proliferate in response to IPH1101 + IL-2, cells from cancer patients often present moderate to very strong impaired proliferative capacity. The reasons for this defect are still unclear, but might result from a suppressive effect induced by the tumour itself. Thus, defective γδ T cell responses might be partly disease-dependent. In some cases, the decreased ability to respond to IPH1101 might also correlate with the stage of the disease or the nature of previous or ongoing treatments. In order to explore in which cancer indications or clinical settings γδ T cell pharmacology is impaired or fully maintained, we have set up a quantitative standardized in vitro “IPH1101 sensitivity test” that requires only a small sample of patient’s PBMC. The objective of this ongoing ex-vivo observational study is to identify types of cancers and settings for which γδ T cell immunotherapy using IPH1101 treatment may be beneficial. Here are reported results from 3 hematological indications: multiple myeloma (MM), follicular lymphoma (FL) and chronic myeloid leukaemia (CML) receiving long term imatinib treatment. Method: Patients with MM, FL and CML have been enrolled at 2 French sites. A small sample of blood (20 mL) is sufficient to prepare PBMCs and culture them in the presence of IPH1101 and IL-2. Results on the extent of in vitro amplification of cells by IPH1101 are available within 8 days and are expressed as % of γδ T cells in the culture and total amplification rate of γδ T cells. Results: Nineteen patients with MM, 31 with FL and 19 with CML receiving imatinib were evaluable in this study. One patient by indication was found strictly not sensitive to IPH1101 stimulation ex vivo, meaning that their γδT cells showed no signs of proliferation in culture. Samples from patients with MM and, to a lesser extent, FL showed a clear impairment of their proliferative response as compared to samples from healthy individuals, with 32% and 10% of MM and FL samples, respectively, demonstrating an impaired response. Finally, in imatinib-treated CML patients, 94% PBMC samples had γδ T cells with full proliferative capacity in response to IPH1101. Conclusion: Ex vivo, γδ T cells from multiple myeloma and follicular lymphoma patients show a low proportion of moderate to strong impairment of their proliferative capacity in response to their specific stimulus IPH1101. For future γδ T cell based immunotherapy trials in these indications, it might be beneficial to consider selecting patients based on such a criteria. In CML patients undergoing long-term treatment with imatinib, γδ T cells have maintained full ability to respond to their specific stimulus (despite the well-known immunosuppressive effects of imatinib). Thus, these results confirm the biological feasibility of combining imatinib and IPH1101 in a clinical trial in CML.

scholarly journals Generation and first characterization of TRDC-knockout pigs lacking γδ T cells

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Bjoern Petersen ◽  
Robert Kammerer ◽  
Antje Frenzel ◽  
Petra Hassel ◽  
Tung Huy Dau ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Mononuclear Cells ◽  
Flow Cytometric Analysis ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Lymphoid Tissues ◽  
Γδ T Cell ◽  
Peripheral Blood Mononuclear

AbstractThe TRDC-locus encodes the T cell receptor delta constant region, one component of the γδ T cell receptor which is essential for development of γδ T cells. In contrast to peptide recognition by αβ T cells, antigens activating γδ T cells are mostly MHC independent and not well characterized. Therefore, the function of γδ T cells and their contribution to protection against infections is still unclear. Higher numbers of circulating γδ T cells compared to mice, render the pig a suitable animal model to study γδ T cells. Knocking-out the porcine TRDC-locus by intracytoplasmic microinjection and somatic cell nuclear transfer resulted in healthy living γδ T cell deficient offspring. Flow cytometric analysis revealed that TRDC-KO pigs lack γδ T cells in peripheral blood mononuclear cells (PBMC) and spleen cells. The composition of the remaining leucocyte subpopulations was not affected by the depletion of γδ T cells. Genome-wide transcriptome analyses in PBMC revealed a pattern of changes reflecting the impairment of known or expected γδ T cell dependent pathways. Histopathology did not reveal developmental abnormalities of secondary lymphoid tissues. However, in a vaccination experiment the KO pigs stayed healthy but had a significantly lower neutralizing antibody titer as the syngenic controls.

scholarly journals β2 Integrins differentially regulate γδ T cell subset thymic development and peripheral maintenance

2020 ◽  
Vol 117 (36) ◽  
pp. 22367-22377
Author(s):  
Claire L. McIntyre ◽  
Leticia Monin ◽  
Jesse C. Rop ◽  
Thomas D. Otto ◽  
Carl S. Goodyear ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Cell Subset ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Γδ T Cell ◽  
Thymic Development ◽  
T Cell Subset

The γδ T cells reside predominantly at barrier sites and play essential roles in immune protection against infection and cancer. Despite recent advances in the development of γδ T cell immunotherapy, our understanding of the basic biology of these cells, including how their numbers are regulated in vivo, remains poor. This is particularly true for tissue-resident γδ T cells. We have identified the β2family of integrins as regulators of γδ T cells. β2-integrin–deficient mice displayed a striking increase in numbers of IL-17–producing Vγ6Vδ1+γδ T cells in the lungs, uterus, and circulation. Thymic development of this population was normal. However, single-cell RNA sequencing revealed the enrichment of genes associated with T cell survival and proliferation specifically in β2-integrin–deficient IL-17+cells compared to their wild-type counterparts. Indeed, β2-integrin–deficient Vγ6+cells from the lungs showed reduced apoptosis ex vivo, suggesting that increased survival contributes to the accumulation of these cells in β2-integrin–deficient tissues. Furthermore, our data revealed an unexpected role for β2integrins in promoting the thymic development of the IFNγ-producing CD27+Vγ4+γδ T cell subset. Together, our data reveal that β2integrins are important regulators of γδ T cell homeostasis, inhibiting the survival of IL-17–producing Vγ6Vδ1+cells and promoting the thymic development of the IFNγ-producing Vγ4+subset. Our study introduces unprecedented mechanisms of control for γδ T cell subsets.

scholarly journals Generation and first characterization of TRDC-Knockout pigs lacking γδ T cells

2021 ◽  
Author(s):  
Bjoern Petersen ◽  
Robert Kammerer ◽  
Antje Frenzel ◽  
Petra Hassel ◽  
Tung Huy Dau ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Mononuclear Cells ◽  
Flow Cytometric Analysis ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Lymphoid Tissues ◽  
Γδ T Cell ◽  
Peripheral Blood Mononuclear

AbstractThe TRDC-Locus encodes the T cell receptor delta constant region, one component of the γδ T cell receptor which is essential for development of γδ T cells. In contrast to peptide recognition by αβ T cells, antigens activating γδ T cells are mostly MHC independent and not well characterized. Therefore, the function of γδ T cells and their contribution to protection against infections is still unclear. Higher numbers of circulating γδ T cells compared to mice, render the pig a suitable animal model to study γδ T cells. Knocking-out the porcine TRDC-locus by intracytoplasmic microinjection and somatic cell nuclear transfer resulted in healthy living γδ T cell deficient offspring. Flow cytometric analysis revealed that TRDC-KO pigs lack γδ T cells in peripheral blood mononuclear cells (PBMC) and spleen cells. The composition of the remaining leucocyte subpopulations was not affected by the depletion of γδ T cells. Genome-wide transcriptome analyses in PBMC revealed a pattern of changes reflecting the impairment of known or expected γδ T cell dependent pathways. Histopathology did not reveal developmental abnormalities of secondary lymphoid tissues. However, in a vaccination experiment the KO pigs stayed healthy but had a significantly lower neutralizing antibody titer as the syngenic controls.

scholarly journals Bovine γδ T-Cell Responses to the Intracellular Protozoan Parasite Theileria parva

1999 ◽  
Vol 67 (5) ◽  
pp. 2241-2249 ◽  
Author(s):  
Claudia A. Daubenberger ◽  
Evans L. N. Taracha ◽  
Laima Gaidulis ◽  
William C. Davis ◽  
Declan J. McKeever
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Lines ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Γδ T Cells ◽  
Theileria Parva ◽  
Γδ T Cell ◽  
Mhc Molecules ◽  
T Cell Lines

ABSTRACT T cells bearing the γδ antigen receptor (γδ T cells) can constitute up to 50% of T cells in the peripheral blood and lymphoid organs of young cattle. We present data showing that γδ T cells are involved in immune responses against Theileria parva. γδ T cells isolated from peripheral blood mononuclear cells (PBMC) of T. parva-naive and -immune cattle proliferated in the presence of fixed or unfixed autologous T. parva-infected lymphoblasts (TpL) and heat-stressed concanavalin A (ConA)-induced blasts (ConA blasts) but not untreated ConA blasts. The specificity of response was further evaluated with a panel of γδ T-cell lines and clones. T-cell reactivity was blocked by GB21A, a monoclonal antibody (MAb) specific for the γδ T-cell receptor, but not by MAbs specific for class I and class II major histocompatibility complex (MHC) molecules. In addition, TpL but not ConA blasts from a variety of MHC-mismatched animals induced proliferation of the γδ T-cell lines and clones. These γδ T cells were found to respond to TpL infected with several different parasite stocks and failed to recognize TpL after elimination of the parasite by the theilericidal drug BW 720C. Assays for cytotoxic activity of γδ T cells sorted from bulk cultures of immune PBMC restimulated several times with autologous TpL demonstrated that effector cells whose specificity is similar to that of proliferating cells are generated. These results suggest that bovine γδ T cells are activated by and lyse T. parva-infected cells by recognizing conserved parasite-induced or parasite-derived antigens in an MHC-unrestricted fashion.

scholarly journals Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses

2020 ◽  
Vol 4 (10) ◽  
pp. 2143-2157 ◽  
Author(s):  
Alak Manna ◽  
Timothy Kellett ◽  
Sonikpreet Aulakh ◽  
Laura J. Lewis-Tuffin ◽  
Navnita Dutta ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Lymphocytic Leukemia ◽  
Dependent Manner

Abstract Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]–like CLL cells) produce high amounts of IL-10 and transforming growth factor β (TGF-β) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-β-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-γ and proliferation of cytotoxic CD8+ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL–patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.

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