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Department of Haematology/Oncology
Freiburg University Medical Centre
There are approximately 76,000 new cases of non-Hodgkin’s lymphoma (NHL) in Europe per year. At least half of these patients will have an indolent NHL that typically exhibits a prolonged disease course but is considered incurable with current standard therapeutic options such as chemotherapy and/or antibody treatment. Only 30–60% of aggressive NHLs can be cured by standard therapy.(1) These facts are driving the search for a less toxic and more targeted therapy that could extend disease-free survival and potentially lead to a cure for the disease.
The B-cell lymphoma cells of one individual express an identical malignant B-cell receptor immuno‑globulin. This tumour-specific antigen, which is called the idiotype, is a perfect target for active immuno‑therapy aimed at inducing specific humoral and cellular immunity, which in turn attacks, fights and eliminates cancer cells.(2) Three multicentre, phase III clinical studies for patients with follicular lymphoma are ongoing, and several phase II studies indicate the advanced clinical development of therapeutic vaccines targeting B-cell lymphomas.(3) These studies will help to identify the preferable clinical conditions and the most susceptible B-cell lymphoma types for vaccination with the idiotype.
Active immunisation against the idiotype elicits protective immunity and cures established lymphoma in mouse models when combined with chemotherapy.(4,5) Several clinical studies, especially in low-grade lymphomas, suggest that active immunotherapy induces a tumour-specific immune response,(6,7) which in turn can lead to tumour regressions and molecular remissions.(8–10) Progression-free survival in patients who showed an anti-idiotype immune response was significantly longer than in patients who did not (7.9 years vs 1.3 years, respectively, p<0.0001).(11) A favourable clinical outcome is also associated with a particular Fcγ receptor genotype, implying that antibody-dependent cellular cytotoxicity (ADCC) mediated by interactions between Fc receptor-bearing natural killer cells and antibody-coated tumour cells is an important immunological effector mechanism.(12) By the end of 2007, results of three phase III trials, including a total of 1,300 patients, are expected. They should help to elucidate the potential and the mechanisms of action of idiotype vaccination in humans more precisely.
The manufacturing of an idiotype vaccine begins with the collection of a tumour sample from the patient by routine biopsy (see Figure 1). Initially, the production of the soluble idiotype protein has been based on a heterohybridoma technique, which is a lengthy and laborious task. Genetic techniques are now yielding recombinant forms of idiotype protein and make large-scale production of idiotype vaccines practical and feasible. GMP-grade production of such a vaccine in E coli is well established and takes approximately three months (see Figure 1), with a success rate of approximately 90%.(7,13) Four companies are currently producing idiotype vaccines for clinical studies for patients with B-cell lymphoma: Biovest (Worcester, MA, USA), generating BiovaxId(®) by heterohybridoma technique; Genitope (Redwood City, CA, USA), producing MyVax(®) using recombinant technology in mouse cells; Favrille (San Diego, CA, USA), producing FavId(®) with baculovirus in Sf9 cells; and CellGenix GmbH (Freiburg, Germany), producing the recombinant protein IdioVax(®) in E coli (see Figure 1). In 2004, EMEA granted to CellGenix GmbH orphan drug designation for the treatment of follicular lymphoma, mantle cell lymphoma and multiple myeloma with IdioVax. Favrille has applied for the orphan designation of its product FavId at the FDA.
Various methods have been implemented to increase the immunogenicity of the idiotype protein. The three US companies prefer the chemical conjugation of keyhole limpet haemocyanin (KLH) to the idiotype protein and inject this conjugate subcutaneously,(4,14) whereas the European idiotype vaccine, produced by CellGenix GmbH, uses MF59, a microfluidised detergent-stabilised oil-in-water emulsion, mixed with the protein, as adjuvant.(15,16) MF59 is part of a licensed influenza vaccine (Fluad(®)), which is already used in more than 20 countries and has demonstrated excellent safety and tolerability in several clinical trials with different antigens.(16) After intradermal injection of the idiotype/MF59 mixture, a very successful enhancement of the immunogenicity to the idiotype protein was demonstrated in patients whose natural immune system activity was reduced substantially due to their disease.(7) All idiotype vaccination trials use the subcutaneous injection of the cytokine GM-CSF close to the injection site of the idiotype/adjuvant protein to enhance T-cell responses by enabling uptake and presentation of the idiotype in dendritic cells.(17) Idiotype vaccination evokes, if at all, mild side-effects such as redness and swelling at the site of injection,(7) as opposed to the known side-effects of all other treatment regimens (chemotherapy, radiation, stem cell transplantation). These very tolerable side-effects are also an important compliance-promoting feature.
Activating the own immune system of individuals affected by malignant B-cell lymphomas to fight remaining tumour cells and maintain clinical remissions is the great potential of therapeutic personalised vaccines. Further clinical studies are ongoing to define the clinical value of personalised tumour vaccines. Most likely, such active immunotherapy will be a complementation to current standard therapies with chemotherapeutic agents and antibodies.