Abstracts of 4th Annual UKMF Scientific Meeting on 07-Feb-2003
Leukaemia Research Fund Lecture: Evolution of immunotherapy in Multiple Myeloma
Nikhil C. Munshi, Dana Farber Cancer Institute, Harvard Medical School, Boston MA
Myeloablative therapies requiring hematopoietic stem cell support can induce complete remissions in up to 40% of multiple myeloma (MM) patients. However, ultimately patients experience disease progression due to the emergence of chemotherapy resistant disease and there is no cure. Novel therapeutic interventions for this disease are therefore needed to specifically target the myeloma cell and its microenvironment. The potential susceptibility of multiple myeloma to immune based therapy has been demonstrated in the allogeneic transplantation through graft versus myeloma effect. A major focus of investigation therefore has been the use of immune-based therapies in a minimal disease setting to decrease risk of relapse and potentially achieve curative outcomes.
The variable regions in immunoglobulin molecule, idiotype (Id), expressed by MM cells, contain determinants that can themselves be recognized as antigens. We have investigated various immunotherapeutic approaches using idiotype as a myeloma-specific antigen. In a clinical protocol involving 49 patients with minimal disease status following tandem autologous transplantation, we utilized patient-specific Id protein coupled with KLH, as a vaccine. The development of an anti-KLH response confirmed immune competence of the myeloma patients. Moreover, induction of Id-specific immune responses including generation of CTL specifically able to lyse MM cells, and a preliminary evidence of a survival benefit was observed.
To improve on these results we have investigated the role of dendritic cells (DCs), the most potent antigen-presenting cells (APCs) equipped with the necessary co-stimulatory, adhesion and MHC molecules, in effectively presenting MM-associated antigens to induce specific immune response. The clinical trials have investigated vaccination with DCs pulsed with tumor associated peptides or proteins in a variety of human cancers. We have evaluated Idiotype-pulsed DC vaccinations in 2 studies involving 25 patients in MM confirming the feasibility of a dendritic cell-based vaccination, development of Id-specific immune responses and even occasional clinical responses. However, robust clinical responses have not been observed, and the strategy targeting single known tumor associated antigens is subject to tumor cell resistance mediated by the down-regulation of that single gene product. Approaches being explored to circumvent this limitation are the DC pulsing with whole myeloma cell lysate, or its RNA, or fusing myeloma cell with DC.
Preclinical results in both a murine model and with human cells confirm feasibility of presenting a wide array of myeloma-related antigens through DC-myeloma cell fusions and the development of CTLs able to lyse primary myeloma cells. A clinical study of MM/DC fusion cell vaccination based on this is ongoing. In conclusion, these stepwise improvements in immunotherapeutic strategies directed at myeloma are likely to lead to immune, and more importantly, clinical responses that will eventually help achieve a cure in multiple myeloma.