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Development of optimised recombinant idiotypic vaccines for subset-specific immunotherapy of B cell lymphomas

Final Report Summary - VITAL (Development of optimized recombinant idiotypic vaccines for subset-specific immunotherapy of B cell lymphomas)

Non-Hodgkin's lymphomas (NHL) are a heterogeneous group of malignancies that still substantially contributes to the incidence of and mortality associated with cancer in Europe. In 2006, NHL accounted for 3.2 % of new cancer cases and 2.8 % of cancer deaths in Europe, making it the 8th leading cause of new cancer cases and the 10th leading cause of cancer deaths. Moreover, European cancer registry data indicate that the incidence of NHL has significantly increased in recent decades. Several lymphoma histotypes, such as mantle cell lymphoma (MCL) and diffuse large B-cell lymphoma (DLBCL), are diseases predominantly found in the elderly population and it has been reported that > 50 % of new NHL cases in Europe and North America occur in patients older than 65 years. Moreover, NHL are emerging as disorders of clinical relevance also for HIV+ patients, as they constitute one of the major causes of death in this setting despite the therapeutic improvement introduced by highly active anti-retroviral therapy.

The main objective of VITAL was the development and production of optimised recombinant Id vaccines for the immunotherapeutic treatment of distinct subset of B cell lymphomas and leukemias.

The most innovative aspect of the VITAL project was constituted by the idea to exploit the molecular features of Id proteins of distinct B cell lymphomas / leukemias, particularly those pathogenically associated with a chronic antigenic stimulation, to develop pre-made, recombinant Id proteins to vaccinate subgroups of lymphoproliferative disorders expressing molecularly correlated idiotypes. Through the synergistic activity of academic and small and medium-sized enterprise (SME) partners, the VITAL project has led to the precise identification of subsets of B cell lymphoproliferative disorders characterised by the expression of molecularly similar Id and thus targetable by pre-made Id vaccines for prevention and treatment purposes. A first set of Id proteins to be used as 'shared' vaccines have been identified and characterised both in vitro and in vivo. Notably, the extensive immunologic characterisation of Id proteins of the VKIII family provided the 'proof of concept' that selected Id proteins may elicit immune responses that cross-react against a broad spectrum of molecularly similar Id expressed by various lymphoproliferative disorders.

These findings indicate that it is now possible to overcome the current complexity and costs due to the individualised production of Id vaccines. The subset-specific vaccines developed within the frames of the VITAL project retain a high selectivity for tumour cells combined with a good tolerability and more affordable costs. A newly developed 'natural' adjuvant, hyaluronic acid, was included in a first vaccine formulation ready for clinical studies. New delivery systems (vaccibodies) able to enhance antigen targeting to antigen presenting cells have been also characterised. The project also led to the development of reagents suitable for the monitoring of idiotype-specific immune responses in the clinical setting (Pentamers, Elispot assays, monoclonal antibodies, etc.). More importantly, from an industrial perspective, the VITAL results open new avenues for European SMEs active in the market of cancer immunodiagnostics and therapeutics.

The VITAL consortium made a great effort to characterise the ability of selected Id proteins to induce specific T cell responses. This is a clinically relevant issue since most of B-NHL patients are currently treated with anti-CD20 monoclonal antibodies, which are known to deplete host B cells thus impairing humoral responses.

The results obtained also indicate that some of the Id vaccines developed may be used not only for the treatment of overtly malignant lymphomas, being administrable also for preventive purposes in defined clinical settings. This is the case of HCV-related cryoglobulinemia, a pre-lymphomatous condition sustained by B cell clones frequently expressing the same Id proteins of HCV-associated lymphomas. Therefore, vaccines targeting these 'shared' Id proteins may reduce the burden of the expanded B cell clones, thus mitigating the symptoms and preventing the evolution of the disease to an overt lymphoma. Identification of several subsets of B cell lymphoproliferations expressing shared Id proteins allowed the estimation of the size of the potential market for the Id vaccines developed. The results so far obtained, particularly those relative to subsets of CLL, suggest that the number of patients treatable with subsetspecific Id vaccines is probably higher than previously hypothesised. A GMPready production and purification process of these recombinant idiotypic proteins has been developed and a first phase I / II clinical trial is expected to start soon after the end of the project.

These pre-made vaccines, once validated as drugs in clinical trials, will have the advantage to be easily distributed to all hematology and oncology departments, including those of peripheral hospitals and universities. Thus, results obtained in the present project will have an important strategic impact in solving, at least in part, the dramatic social and health problem represented by NHL. Finally, a strong network between European research institutions and industry has been established opening new cooperation possibilities in the field of cancer vaccines.

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