IdiotypeVaccination Strategies in Myeloma : How to Overcome a Dysfunctional Immune System 55

In this issue of Clinical Cancer Research , Hansson et al. vaccinated 28 patients (IgG myeloma, Salmon-Durie stages I and II) with autologous myeloma idiotype protein and assessed the effect of adding either granulocyte macrophage colonystimulating factor (GM-CSF) alone or the combination of GMCSF and interleukin 12 (IL-12) during the vaccination program (1). Idiotype-specific T-cell responses as measured by proliferation and ELISPOT assays, and delayed-type hypersensitivity reactions were more frequent in patients receiving GM-CSF and IL-12 compared with those treated with IL-12 alone (85% versus 33%). The median time to myeloma progression was 108 weeks in immunologic responders compared with 26 weeks for nonresponders, which provides the first tentative evidence that idiotype vaccination in myeloma may translate into clinical benefit. Immunologic nonresponse was associated with an increase in CD4/CD25/Foxp3 cells (Treg cells). The immunogenicity of the idiotype protein in myeloma has been investigated for more than three decades (2). Vaccination with the idiotype protein is attractive because it provides for multiple patient-specific tumor epitopes which can be readily purified from the peripheral blood of patients with myeloma. The idiotype protein can induce humoral immunity, however, in contrast to lymphoma, myeloma cells do not express the IgG idiotype on the cell surface, and hence, the contribution of idiotype antibodies to any vaccine-induced clinical responses in myeloma is unclear. The immunogenic peptides contained in idiotypes are mostly derived from the variable CDRI, II, and III regions rather than the framework region of the IgG molecule inducing CD4 and CD8 T cell immune responses (3, 4). Idiotype-pulsed dendritic cells (DC) can induce autologous idiotype-specific T cells from patients with myeloma, which have the ability to kill primarymyeloma cells. This proves that idiotypes are indeed naturally processed andpresented bymalignant plasma cells (5). Cytolysis of myeloma cells is mostly HLA class I– restricted andmediated via the perforin/granzymemechanism (5). Naturally occurring idiotype-specific T cells are present in monoclonal gammopathy of underdetermined significance and multiple myeloma, and were also detected in the present study. However, in advanced myeloma, the T cell responses may be shifted to type 2 inflammatory cellular responses (6, 7). This pool of preexisting idiotype-specific T cells could potentially be expanded by vaccination with idiotype proteins, but the functional activity of these T cells is a matter of debate. Active immunization in experimental animal models provides protection against challenge with myeloma tumor cell lines (2, 8). However, results in human clinical trials with idiotype vaccination have thus far been disappointing. Immunologic responses occur in <50% of patients and clinical responses are rare (9). Perhaps this is because idiotype proteins are weak immunogens and induce only weak to intermediate affinity T cells. There have been attempts to enhance immune responses by linking idiotypes to keyhole limpet hemocyanin or tetanus toxoid in order to recruit helper T cells (10). Others have added GM-CSF at the site of injection to attract DCs and promote the processing and presentation of idiotype antigens (11). GM-CSF seems to be a critical component of vaccination regimens in lymphoma, which have clinical efficacy (12, 13). Clinical trials with ex vivo idiotype–pulsed DCs have not been successful either, which in part, can be explained by the use of immature DCs and/or the i.v. administration of DCs (14). In addition, vaccination with immature DCs may favor the induction of Tr1-like regulatory T cells (15, 16). In patients with myeloma, DCs are functionally abnormal in vivo and exhibit an immature phenotype with reduced expression of the costimulatory molecule B7.1 (17). These DCs have a reduced ability to stimulate antigen-specific T cells and present patientspecific idiotype proteins to autologous T cells (18). Excess secretion of transforming growth factor h, IL-6, and IL-10 by myeloma cells and/or the myeloma microenvironment are responsible for these abnormalities (17, 18). Transforming growth factor h and IL-10 can induce tolerance of antigenspecific T cells and skew the immune response to a type 2 T-cell response. IL-6 is also an autocrine and paracrine growth factor for myeloma cells and inhibits the development of DCs from CD34 progenitor cells (18). The number of high-potency DCs is lower with more advanced myeloma disease (18, 19). The level of h2 microglobulin reflects tumor burden and is a poor prognostic factor in the International Staging System. h2 Microglobulin also has detrimental effects on DC function and reduces IL-12 production by monocyte-derived DCs. h2 Microglobulin reduces the expression of costimulatory and adhesion molecules by DCs and negatively affects the induction of T cell responses (20). Furthermore, it has recently been reported that DCs may directly support the clonogenic growth of primary myeloma cells (21). Taken together, these observations emphasize the ability of myeloma to dysregulate the function of ex vivo and in vivo generated DCs and helps to explain the poor clinical results of idiotype vaccination trials. It is of interest to note that in the study by Hansson et al., the number of baseline CD4/CD25/Foxp3 Treg cells in immunologic responders was lower compared with nonresponders. In two-thirds of the immune responders, the immune response The Biology Behind