Soluble LAG-3 Protein is a Prognostic Factor in Breast Cancer
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Immutep S.A. has announced the publication of a research paper showing that soluble LAG-3 (Lymphocyte Activation Gene-3) protein (sLAG-3) is a prognostic indicator for survival in breast cancers expressing oestrogen or progesterone receptors.
The results pave the way for the testing of a recombinant sLAG-3 protein as an adjuvant therapy for breast cancer in clinical trials.
The study (Cancer Letters 235 (2006) 147-153) was carried out by Dr Marie-France Pichon and Kamel Hacene of the René Huguenin Cancer Centre in Saint-Cloud, near Paris, and Pr. Frederic Triebel when he was at the Pharmacy Faculty of University Paris XI.
In contrast to the long-held belief that breast cancer is a weakly immunogenic tumour, accumulating evidence indicates that an immune infiltrate is an invariable finding in breast cancers; raising hopes that immunotherapy may succeed in targeted patients, specifically those with either regional or minimal residual disease.
However, no immunologically-related prognostic factor has yet been established that may help to define subsets of patients who are more prone to respond to immunotherapy.
High levels of soluble LAG-3 protein (sLAG-3) in sera have previously been shown to be associated, as a Th1 marker, with resistance to tuberculosis in large series of patients.
The researchers therefore hypothesized that, if cell-mediated immune mechanisms are indeed important for improved prognosis, high levels of sLAG-3 might be correlated with improved survival in some subsets of breast cancer patients.
Studying a cohort of 246 patients' sera collected in 1994 at the time of first diagnosis, it was found that both disease-free and overall survival rates were higher in those patients with oestrogen or progesterone receptor positive tumour cells who had detectable levels of sLAG-3 at diagnosis than in patients with undetectable sLAG-3 levels.
These results indicate that sLAG-3 may be a valuable marker for prognosis in some subsets of breast cancers and, more importantly, that cell-mediated mechanisms such as Th1 responses do have an impact on survival, a prerequisite before the setting up of immunotherapy protocols as a form of adjuvant therapy for breast cancer.
"These results shed new light on the importance of cellular immunity in breast cancer and warrant new efforts in using immunotherapy as an add-on to conventional chemotherapy in advanced breast cancer," said Pr. Jean-Nicolas Munck, Director of the Rene Huguenin Cancer Centre whose Oncobiology Laboratory and Medical Statistics Service carried out the clinical part of the study.
The LAG-3 analyses were performed at the Pharmacy Faculty of University Paris XI.
"It is striking that whatever the stage of the disease in 1994 and the type of subsequent therapy, we were able to show that high levels of sLAG-3 in the ng/ml range in the sera collected at diagnosis are associated with a much better outcome 10 years later," said Frederic Triebel.
"These results have encouraged us to mimic nature's work by directly injecting in patients a recombinant sLAG-3 protein, termed IMP321, without any tumour antigen, as a first line therapy in mostly incurable diseases such as metastatic renal cell or breast carcinomas."
Soluble LAG-3 is a circulating form of LAG-3 derived by an alternative splicing event.
LAG-3 was discovered by Frédéric Triebel and is 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 Rene Huguenin Cancer Centre are planning to conduct clinical trials with the Company's sLAG-3 immunostimulatory factor, ImmuFact® IMP321, in conjunction with chemotherapy, later in the year.
Apart from the research work and clinical trials discussed here, the René Huguenin Cancer Centre has no other links with Immutep and no member of its staff has a financial interest in the Company.
