Immunotherapy and allogeneic transplantation: targetting the B cell hierarchy

Workpackage 15

Subject

Optimisation of immunotherapeutic approaches including allogeneic stem cell transplantation (allo-SCT) for MM.

Present Status

High-dose therapy followed by autologous transplantation has improved survival in MM, however all patients eventually relapse, indicating the need for consolidation. Activation of idiotype-specific T cells by vaccination with autologous tumorprotein-loaded dendritic cells has been demonstrated. So-called Vaccibodies (consisting of two scFv (single chain Fragment variable) specific for surface molecules on APC (MHCII, CD40) linked to two exchangeable scFv from the mouse M315 myeloma protein and a Cγ3 dimerizing domain) elicit anti-Id antibodies in mice even in the absence of adjuvant, and stimulate Id-specific CD4+ T cells in vitro. The clinical potency of idiotype specific immunity still needs to be evaluated. Other potential antigens for immunotherapy of multiple myeloma are CD19, CD20, CD38, CD54, CD138, MAGE-antigens, Sperm-17, MUC1 core protein or HM1.24.

Allo-SCT is currently the only potentially curative treatment. Although considered the most effective immunotherapy, allo-SCT is a risky procedure with a high treatment-related mortality, which need to be reduced. Novel approaches with low-dose or nonmyeloablative (NMA-) conditioning, combined with programmed infusion of donor lymphocyte (DLI) have shown promising results. In addition it is expected that passive (antibody) and active (vaccination) immunotherapy have some anti-myeloma activity, especially in patients with a low tumor burden. Patients lacking a suitable donor for allo-SCT programmes can be ideal candidates for vaccination programmes.

Preview of Programme Proposed

• Identification of new target antigens for a myeloma-specific immunotherapy using results from the gene expression profiling project, characterization of new T cell epitopes within these antigens, characterization of antibody responses against these new antigens.
• Test Vaccibodies in mice and humans (application as naked plasmids intra muscularly, possibly combined with electroporation).
• Phase I-II safety and toxicity studies of NMA regimens (incorporating melphalan, fludarabine, ATG, Campath-1H, and TBI) and related and unrelated donor allo-SCT regarding TRM, toxicity, GvHD.
• Assessment of schedules for DLT.
• Assess function and therapeutic uses of allogeneic stem cells, including cells derived from bone marrow, peripheral blood, and cord blood.
• Correlation of clinical outcome after immunotherapy/allo-SCT with common prognostic factors and global gene expression patterns as defined by microarray, to assess which groups of patients benefit most from what kind of therapy.
• Evaluation of monitoring techniques (chimerism analysis, clone-specific PCR to quantify minimal residual disease) as potential tools for guiding therapeutic decisions on indication for allo-SCT, use of DLT, and immunosuppression.
• Evaluation of quality-of-life issues

Deliverables and Cooperations

• Selected antibodies and vaccination targets to be tested in phase II and III clinical trials.
• Generation of Vaccibodies for human use
• Improved allo-SCT with reduced TRM.
• Risk-adapted therapy strategy for the treatment of MM.