IMP321 (sLAG-3), an immunopotentiator for T cell responses against a HBsAg antigen in healthy adults: a single blind randomised controlled phase I study

Brignone, Chrystelle; Grygar, Caroline; Marcu, Manon; Perrin, Gaëlle; Triebel, Frédéric

doi:10.1186/1476-8518-5-5

Cited by 32 publications

(24 citation statements)

References 16 publications

(15 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…PBMCs were incubated with or without IMP321 (1 g/ml) or TLR agonists (optimal concentrations): TLR1-2, TLR3, TLR4, TLR5, TLR6-2, TLR7-8, or TLR9 agonists for 24 thrombosis due to platelet activation (38) but CD40 agonist therapeutic Abs are now being tested in cancer patients. IMP321 has been shown to be safe and well-tolerated in several phase I/II trials (www.clinicaltrials.gov/) (24,39) and immunomonitoring will reveal whether some of the effector cell subsets described in the present study are indeed activated in vivo.…”

Section: Figure 6 Specific and Indirect Cd8mentioning

confidence: 99%

“…The percentages of CD3 ϩ CD4 ϩ , CD3 ϩ CD8 ϩ T cells, and CD3 Ϫ CD8 ϩ NK cells expressing one, two, or three of these cytokines were determined. The measurement of cytokine ϩ cells using this procedure has been validated previously and gives an overall coefficient of variation Ͻ20% after Ag-specific stimulation (24). A slight increase in cytokine-expressing CD4 ϩ T cells was detected in 44 (of 60) PBMCs stimulated with IMP321 compared with medium alone.…”

Section: Imp321 Induces Cd8 ϩ T Cells and Nk Cells To Produce Cytokinmentioning

confidence: 99%

See 1 more Smart Citation

A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells

Brignone

Grygar

Marcu

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

The principal antitumor immune response is mediated through the activation of type 1 cytotoxic (Tc1) CD8 T cells, NK cells, and monocytes/macrophages. In this study, we investigated the potency of a clinical-grade soluble form of lymphocyte activation gene-3 protein (IMP321), a physiological high-affinity MHC class II binder, at inducing in PBMCs an appropriate cytotoxic-type response in short-term ex vivo assays. We found that IMP321 binds to a minority (<10%) of MHC class II + cells in PBMCs, including all myeloid dendritic cells, and a small fraction of monocytes. Four hours after addition of IMP321 to PBMCs, these myeloid cells produce TNF-α and CCL4 as determined by intracellular staining. At 18 h, 1% of CD8+ T cells and 3.7% NK cells produce Tc1 cytokines such as IFN-γ and/or TNF-α (mean values from 60 blood donors). Similar induction was observed in metastatic cancer patient PBMCs, but the values were lower for the NK cell subset. Early APC activation by IMP321 is needed for this Tc1-type activation because pure sorted CD8+ T cells could not be activated by IMP321. Only Ag-experienced, fully differentiated granzyme+ CD8 T cells (effector and effector memory but not naive or central memory T cells) are induced by IMP321 to full Tc1 activation. In contrast to IMP321, TLR1-9 agonists induce IL-10 and are therefore unable to induce this Tc1 IFN-γ+ response. Thus, IMP321 has many properties that confirm its potential to be a new class of immunopotentiator in cancer patients.

show abstract

Section: Figure 6 Specific and Indirect Cd8mentioning

confidence: 99%

Section: Imp321 Induces Cd8 ϩ T Cells and Nk Cells To Produce Cytokinmentioning

confidence: 99%

A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells

Brignone

Grygar

Marcu

et al. 2007

The Journal of Immunology

Self Cite

View full text Add to dashboard Cite

show abstract

“…CD40L has been tested in phase I trials (4) but clinical development has been stopped due to secondary effects such as thrombosis induction (its receptor, CD40, is also expressed on platelets and endothelial cells). Thus, the soluble LAG-3Ig fusion protein (or IMP321) is the only protein that is presently available for this therapeutic approach (5)(6)(7)(8).…”

mentioning

confidence: 99%

A Phase I Pharmacokinetic and Biological Correlative Study of IMP321, a Novel MHC Class II Agonist, in Patients with Advanced Renal Cell Carcinoma

Brignone¹,

Escudier²,

Grygar³

et al. 2009

Clinical Cancer Research

Self Cite

195

112

View full text Add to dashboard Cite

Purpose: To evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of IMP321, a recombinant soluble LAG-3Ig fusion protein which agonizes MHC class II-driven dendritic cell activation. Experimental Design: Patients with advanced renal cell carcinoma were treated with escalating doses of IMP321 s.c. Blood samples were assayed to determine plasma pharmacokinetic parameters, detect human anti-IMP321 antibody formation, and determine long-lived CD8 T cell responses.

show abstract

“…The safety and toxicity profile of IMP321 has been established in two randomized phase I trials of subcutaneous vaccination against Influenza virus (Flu, n ¼ 60) and the Hepatitis virus (HBsAg, n ¼ 48) in healthy volunteers (14,15). Both studies revealed very good clinical tolerability with a low toxicity profile for the four dose levels of IMP321: 3, 10, 30, and 100 mg. Mage-A3/DP4-specific CD4 T-cells from patient Lau 1187 showing two phenotypes with tetramer-high and tetramer-low staining.…”

Section: Discussionmentioning

confidence: 99%

“…Consequently, it enhances specific immune responses, by stimulation of antigen cross presentation to CD8 T-cells, and by decreasing regulatory T-cell frequency and function (9). Clinical trials with IMP321 showed already promising results when used as adjuvant for vaccination against hepatitis B and influenza viruses in healthy individuals (14,15). Several trials have provided evidence for clinical activity in patients with advanced renal cell carcinoma, metastatic breast carcinoma, and metastatic melanoma (16)(17)(18).…”

Section: Introductionmentioning

confidence: 99%

Vaccination with LAG-3Ig (IMP321) and Peptides Induces Specific CD4 and CD8 T-Cell Responses in Metastatic Melanoma Patients—Report of a Phase I/IIa Clinical Trial

Legat

Hajjami

Baumgaertner

et al. 2016

Clinical Cancer Research

Self Cite

View full text Add to dashboard Cite

Purpose: Cancer vaccines aim to generate and maintain antitumor immune responses. We designed a phase I/IIa clinical trial to test a vaccine formulation composed of Montanide ISA-51 (Incomplete Freund's Adjuvant), LAG-3Ig (IMP321, a non-Toll like Receptor agonist with adjuvant properties), and five synthetic peptides derived from tumor-associated antigens (four short 9/10-mers targeting CD8 T-cells, and one longer 15-mer targeting CD4 T-cells). Primary endpoints were safety and T-cell responses.Experimental Design: Sixteen metastatic melanoma patients received serial vaccinations. Up to nine injections were subcutaneously administered in three cycles, each with three vaccinations every 3 weeks, with 6 to 14 weeks interval between cycles. Blood samples were collected at baseline, 1-week after the third, sixth and ninth vaccination, and 6 months after the last vaccination.Circulating T-cells were monitored by tetramer staining directly ex vivo, and by combinatorial tetramer and cytokine staining on in vitro stimulated cells.Results: Side effects were mild to moderate, comparable to vaccines with Montanide alone. Specific CD8 T-cell responses to at least one peptide formulated in the vaccine preparation were found in 13 of 16 patients. However, two of the four short peptides of the vaccine formulation did not elicit CD8 T-cell responses. Specific CD4 T-cell responses were found in all 16 patients.Conclusions: We conclude that vaccination with IMP321 is a promising and safe strategy for inducing sustained immune responses, encouraging further development for cancer vaccines as components of combination therapies.

show abstract

IMP321 (sLAG-3), an immunopotentiator for T cell responses against a HBsAg antigen in healthy adults: a single blind randomised controlled phase I study

Cited by 32 publications

References 16 publications

A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells

A Soluble Form of Lymphocyte Activation Gene-3 (IMP321) Induces Activation of a Large Range of Human Effector Cytotoxic Cells

A Phase I Pharmacokinetic and Biological Correlative Study of IMP321, a Novel MHC Class II Agonist, in Patients with Advanced Renal Cell Carcinoma

Vaccination with LAG-3Ig (IMP321) and Peptides Induces Specific CD4 and CD8 T-Cell Responses in Metastatic Melanoma Patients—Report of a Phase I/IIa Clinical Trial

Contact Info

Product

Resources

About