May 11 2011
Cytheris SA, a clinical stage biopharmaceutical company focused on research and development of new therapies for immune modulation, the Centre Léon Bérard (Lyon), the major cancer research and treatment center for the Rhône-Alpes region of France, and ImmunID Technologies SAS (Grenoble), a diagnostic company specialized in innovative immunomonitoring tests and services, today announced initiation of a Phase IIa clinical trial that will evaluate multiple combinations of recombinant human interleukin-7 (CYT107), the investigational multifunctional cytokine under development by Cytheris, and a chemotherapeutic agent, XELODA® (capecitabine, Roche/Genentech), in the treatment of metastatic breast cancer.
The trial is designed to explore the optimal schedule for delivery of CYT107 during standard capecitabine chemotherapy, with the aim of immune reconstitution and collection of preliminary data on the impact of CYT107 on severe hematological toxicity and tumor progression in second line metastatic breast cancer patients. The immunorestorative properties of IL-7, which include its ability to provide T cells to attack any residual disease, are expected to have a significant impact on survival in this patient population, where a low CD4 T cell count associated with poor receptor diversity detected before initiation of chemotherapy is a known predictive factor indicating overall survival of less than 6 months compared to almost two years for non-lymphopenic patients.
Conducted as a collaborative effort of the Centre Léon Bérard (the study sponsor), ImmunID Technologies, and Cytheris, the study, known as ELYPSE-7, is designed to evaluate whether CYT107 treatment is able to correct lymphopenia post-chemotherapy in advanced cancer patients and whether the correction of this lymphopenia by restoration of the immune system will result in a broadening of the repertoire of T cells and a reduction in the risk of severe haematological toxicity, tumor progression and early death.
The study is based on many years of research conducted by the team of Jean-Yves Blay, MD, PhD, Professor of Medicine at the Université Claude Bernard, Lyon, and the current President of the European Organization for Research and Treatment of Cancer (EORTC).
"Lymphopenia (<1000 Lymphocytes/μl) or CD4+ T cell lymphopenia (<450/μl) detected prior to initiation of chemotherapy as well as Divpenia® (low diversity of the T cell repertoire) are known to be predictive factors for toxicity and death in patients with metastatic solid tumors. Correction of this condition through an immunotherapeutic approach would therefore represent a potential paradigm shift in the treatment of patients with various types of cancer," commented Dr. Blay. "In the SEMTOF trial, which included a total of 70 metastatic breast cancer patients in first line treatment, a low T cell receptor (TCR) repertoire diversity (Divpenia®, as defined and measured by ImmunID Technologies) was associated with a short overall survival of ≤6 months. Median survival of severely divpenic patients was less than 6 months, compared to >22 months for the remaining patients who were not in this severely lymphopenic state. The outcome of the ELYPSE-7 study is thus expected to have significant implications for overall survival and tumor progression in patients with advanced cancers, including ovarian cancer, metastatic breast cancer, non-Hodgkin lymphoma, and sarcoma."
Qualitative and quantitative alterations of local and circulating immune cells have been identified as playing an important role in breast cancer progression. In a series of studies including more than 3000 patients, Dr. Blay's team has shown that lymphopenia is found in 20-25% of patients with advanced cancers, including 20% of untreated patients with metastatic breast cancer. In a large series of patients it was observed that lymphopenia is associated with a 20% and 50% risk of early death at 1 and 3 months and that T cell CD4 lymphopenia is also an independent risk factor for early death and toxicity in these patients.
"In a recent review article (Mackall C et al. Nat Rev Immunol. 2011 May; 11(5):330-42) entitled "Harnessing the Biology of IL-7 for Therapeutic Application", the authors conclude that despite the impressive biological effects of IL-7 on T cell populations, the essential issue regarding clinical development of this cytokine is the need to show that the biological effects of IL-7 translate to improved clinical outcomes such as prolonged survival or cure," said Michel Morre, DVM, President and CEO of Cytheris. "Such proof of concept can only be obtained by carrying out careful clinical trials in targeted populations who are at greatest risk owing to T cell immunodeficiency, precisely the goal of the ELYPSE-7 study."
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