Tumor Antigen Immunization of Sibling Stem Cell Transplant Donors in Multiple Myeloma

Strategies to enhance the specific anti-tumor effect of the graft without increasing the risk of graft-versus-host disease (GVHD) are needed to improve the outcome in allotransplant recipients. In this pilot study, we vaccinated sibling donors against a defined, patient tumor-derived antigen prior to bone marrow harvest. The objective of this strategy was to induce tumor antigen-specific immunity in healthy donors and to transfer this immunity to the recipients by bone marrow transplantation (BMT). For this purpose, the unique antigenic determinants (Idiotype [Id]) of the immunoglobulin secreted by the myeloma tumor can serve as a safe, tumor-specific antigen for active immunotherapy. The vaccine formulation consisted of Id isolated from the plasma of myeloma patients chemically conjugated to a carrier molecule keyhole limpet-hemocyanin (KLH) and administered together with GM-CSF as an adjuvant. Immunization of the HLA-matched sibling donors (n = 5) prior to bone marrow harvest, induced specific cellular and/or humoral immune responses against Id and KLH in all five donors. No short-term or long-term toxicities were observed in any of the donors following vaccination. The recipients received priming vaccination pretransplant and booster immunizations starting approximately 3 months after the myeloablative transplantation. Following BMT, two patients died within 30 days due to transplant related complications. Id-specific and KLH-specific T cell responses were detected in all three surviving patients post-, but not pre-BMT. In at least one patient, Id-specific T cell immunity persisted beyond 18 months after completion of the vaccination schedule. All three surviving patients converted from a partial response to a complete response following BMT. Two of the three patients (both recipients of immune BMT from syngeneic twins) remain in complete remission 8 years and 7 years after the transplant, and the third patient developed chronic steroid-dependent GVHD and died of renal failure after 5.5 years while in complete remission from the disease. Our results suggest that Id vaccination induces specific T cell immunity in the donors that is transferable by BMT, is associated with a prolonged disease-free survival in recipients and may represent a novel strategy to enhance the graft versus myeloma effect. These encouraging results have prompted us to initiate a clinical trial to evaluate this approach of donor immunization in the context of non-myeloablative allogeneic peripheral blood stem cell transplantation in myeloma patients.