Novel immunotherapies

Abstract

Multiple myeloma is still a fatal disease. Despite advances in high-dose chemotherapy and stem-cell transplantation and the development of novel therapeutics, relapse of the underlying disease remains the primary cause of treatment failure. Strategies for posttransplantation immunomodulation are desirable for eradication of remaining tumor cells. To this end, immunotherapy aimed at inducing myeloma-specific immunity in patients has been explored. Idiotype protein, secreted by myeloma cells, has been the primary target for immunotherapy as it is the best defined tumor-specific antigen. This chapter focuses on novel immunotherapies that are being developed to treat patients with myeloma. I will discuss potential myeloma antigens, antigen-specific T cells, and their function on myeloma tumor cells, and T-cell-based and antibody-based immunotherapies for myeloma. Furthermore, clinical studies of T-cell-based immunotherapy in the form of vaccination, allogeneic stem-cell transplantation and donor lymphocyte infusions, with or without donor vaccination using patient-derived idiotype, and future application of donor-derived or patient-derived, antigen-specific T-cell infusion in this disease are also discussed. Based on the specificity of the immune effector molecules and cells, immunotherapies with specific T cells or therapeutic antibodies may represent novel strategies for the treatment of multiple myeloma in the near future.

Figure 1. Cytotoxicity of DKK1 peptide-specific T-cell clones

P20-specific or P66-specific T-cell clones against human myeloma cell lines U266 (DKK1⁺/HLA-A*0201⁺) and ARP-1 (DKK1⁺/HLA-A*0201⁻), and primary myeloma cells from four patients with MM (MM1 to MM4). Control target cells include normal mesenchymal stem cells (MSCs), DCs, B cells, and PBMCs from HLA-A*0201⁺ healthy donors. Patients #1 and #2 were HLA-A*0201⁺, and patients #3 and #4 were HLA-A*0201̃. All primary myeloma cells expressed DKK1 protein. P20 and P66 are two DKK1 peptides that have high affinity for HLA-A*0201. An effector:target (E:T) ratio of 10:1 was used. Results of four independent experiments with two CTL clones generated from a patient with MM are shown.

Figure 2

In vivo therapeutic effects of β₂M-specific mAbs on established human myeloma in a SCID mouse model. Mice were xenografted subcutaneously with ARP-1, and tumor burdens were monitored as tumor volumes. Mice received intraperitoneal injections every 3 days for a total of 4 injections of 250 µl ascites containing about 500 µg D1 β₂M-specific mAb or 500 µg mouse IgG1, or an equal volume of PBS. Results (image of tumor burdens in the mice) from one representative experiment out of three performed using D1 mAb with 5 mice per group are shown.