Soluble LAG-3 molecule amplifies tumor-specific immunity

Immutep S.A. announced today the publication of a research paper showing that a soluble human LAG-3 protein amplifies the in vitro generation of type 1 tumor-specific immunity.

The study (Cancer Research 2006; 66: (8): 4450-60) was carried out by Chiara Castelli and coworkers in Pr. Giorgio Parmiani's group of Italy's National Tumor Institute in Milan. This group has belonged to the top tier of European tumor immunology groups for more than 20 years, in terms of both basic and clinical research activities.

The adjuvant activities of the human Lymphocyte Activation Gene-3 (LAG-3) molecule were evaluated in a human setting by investigating the ability of a soluble recombinant human LAG-3 protein (hLAG-3Ig) to enhance the in vitro induction of viral and tumor-specific CD8+ cytotoxic T lymphocytes (CTLs). The researchers found that soluble human LAG-3 significantly sustained the generation and expansion of CD8+ T lymphocytes against influenza matrix protein antigen or tumor antigens (Melan-A/MART-1 and survivin) in peripheral blood mononuclear cells (PBMCs) of healthy donors or cancer patients.

This shows that hLAG-3Ig has a unique ability to prime naïve CD8+ T cells against a new antigen and to boost antigen-specific CD8+ T cell memory response in vitro. The peptide-specific T cells generated in the presence of hLAG-3Ig were endowed with cytotoxic activity, enhanced release of type-1 cytotoxic T (Tc1) cytokines and were able to recognize tumor cells expressing their nominal antigen. Phenotype and cytokine/chemokines produced by antigen presenting cells (APC) in PBMCs exposed in vitro for 2 days to hLAG-3Ig indicate that the LAG-3-mediated adjuvant effect may depend on direct activation of circulating APCs.

The data revealed the activity of hLAG-3Ig in inducing tumor-associated, antigen-specific CD8+ T cell responses in a human setting and strongly support the conclusion that this recombinant protein is a potential candidate adjuvant for cancer vaccines.

“These results taught us that a soluble human receptor protein, which is not a TLR agonist or a cytokine, could be used to expand tumor-specific CTL in humans, paving the way to its use as a cancer vaccine adjuvant”, said Professor Giorgio Parmiani, Director of the Unit of Immunotherapy of Human Tumors of the National Tumor Institute in Milan.

The hLAG-3Ig, in the form of IMP321 (a GMP-grade recombinant protein), was supplied by Immutep. “Following years of preclinical and now clinical studies, these results are a direct proof that IMP321 is a powerful immunostimulant for patients' blood cells,” said Frédéric Triebel, the Company's Scientific and Medical Director. “These results have encouraged us to conduct several clinical trials with repeated s.c. injections of IMP321 mixed with numerous tumor antigen epitopes in patients with mostly incurable diseases, including advanced melanoma and ovarian cancer.”

LAG-3 was discovered by Frédéric Triebel and is a key mediator of the immune system expressed on the surface of activated T cells. Immutep has an exclusive licence to the molecule and related applications.

Immutep and the National Tumor Institute are planning to conduct a clinical trial in metastatic melanoma with the Company's sLAG-3 immunostimulatory factor, ImmuFact^® IMP321, associated with peptide epitopes. Apart from the research work discussed here, the National Tumor Institute in Milan has no other links with Immutep and no member of its staff has a financial interest in the Company.

For further information please visit the web-site www.immutep.com or e-mail John Hawken, CEO, at JBHawken@immutep.com.