Abstract A37: Identification of a gene expression signature predictive of clinical activity following MAGE-A3 ASCI treatment
Authors: Louahed Jamila , Lehmann Frederic , Ulloa-Montoya Fernando , Gruselle Olivier , Dizier Benjamin , Vansteenkiste Johan , Kruit Wim , Brichard Vincent 
Published: June 2012

Clinical data today highlight the encouraging potential of the MAGE-A3 Antigen-Specific Cancer Immunotherapeutic (ASCI) for cancer treatment. The MAGE-A3 gene encodes a tumor-specific antigen expressed on tumor cells only. When used as a recombinant protein and combined with an immunological Adjuvant System designed to enhance the immune response to the MAGE-A3 antigen, it was shown to induce specific T-cell responses and long-lasting clinical objective responses in metastatic melanoma (Phase II NCT00086866 trial) (Kruit et al. JCO 2008 26:9065), and demonstrated proof-of-concept in Non-Small Cell Lung Cancer (NSCLC; Phase II NCT00290355 trial) (Vansteenkiste et al. JCO 2007 25:7554).

In these 2 trials, gene expression profiling by microarrays was used to identify biomarkers predictive of the clinical activity of the MAGE-A3 ASCI. A first analysis carried out on samples from melanoma patients using supervised hierarchical clustering of 2 objective responders and 2 non-responders identified 2 gene clusters based on differential gene expression. This immune gene expression signature was then confirmed in an analysis of 22-patient samples, and independently validated on an additional 30-patient testing set; furthermore these analyses confirmed the association of clinical benefit and the molecular signature.

Most of the identified genes are immune-related, defining a particular biological context present in the tumor environment before immunization. This was confirmed by selecting genes using all patients eligible for gene expression profiling. Upon crossvalidation, median overall survival was improved significantly in the population of patients whose tumor presented the gene signature (GS): 28 months in the GS+ population, 16.2 months in the GS−. The predictive value of the melanoma signature was tested in NSCLC. A subset of 49 genes discovered in the melanoma Phase II trial was assayed by qPCR on biopsies taken prior to any ASCI treatment from 137 patients of the lung Phase II trial. Applied to NSCLC patients, this biomarker showed that the relative reduction in the risk of recurrence upon MAGE-A3 ASCI treatment is increased by about 2 fold in the patients with the predictive gene signature as compared to the overall population: from 25% relative improvement in the overall population to 53% in patients whose tumor presents the predictive gene signature. In conclusion, two clinical proof-of-concepts have been obtained with the MAGE-A3 ASCI in 2 different types of tumors, NSCLC and melanoma. More importantly, we have identified a gene expression signature predictive of clinical activity of the MAGE-A3 ASCI treatment. The initiation of Phase III studies in NSCLC (MAGRIT) and melanoma (DERMA) is a unique opportunity to validate prospectively these biomarkers with the ultimate goal to select patients that are the most likely to benefit from the MAGE-A3 ASCI therapy.

Citation Information: Mol Cancer Ther 2009;8(12 Suppl):A37.