Tumor antigen immunization of sibling stem cell transplant donors in multiple myeloma

Abstract

Summary:The unique antigenic determinants (idiotype (Id)) of the immunoglobulin secreted by myeloma tumor can serve as a tumor-specific antigen for active immunotherapy. Our objective was to induce tumor-specific T-cell immunity in bone marrow transplant (BMT) donors to enhance antitumor effects of allografts. We vaccinated five HLAmatched sibling donors with myeloma Id proteins isolated from recipient plasma before bone marrow harvest. Recipients were administered booster Id immunizations following transplantation. Vaccination induced donor Id and carrier-specific cellular and/or humoral immune responses. Two recipients died within 30 days of BMT from transplant-related complications. Id and carrierspecific T-cell responses were detected in all three remaining patients post-, but not pre-BMT and persisted for 18 months. All three surviving patients converted from partial to complete responses following BMT. Two of the three patients remain disease-free 7 years and 8 years after BMT, and the third died of renal failure after 5.5 years while in complete remission from myeloma. Our results suggest that myeloma Id vaccination induces specific T-cell immunity in healthy donors which may be transferable by BMT, is associated with prolonged disease-free survival of recipients, and may represent a general strategy to enhance graft-versus-tumor effect in other malignancies for which defined tumor-specific antigens exist.

Adoptive T cell therapy for cancer in the clinic

“…In mice, adoptive T cell therapy enhances the effects of therapeutic vaccines (34,35), and this combined approach in the setting of lymphopenia results in a further enhancement of tumor immunity compared with combined treatment in lymphoreplete hosts (36,37). In humans with myeloma, idiotype vaccination of sibling donors with the unique tumor-specific Ig produced by the patient's myeloma cells followed by adoptive transfer in the setting of allogeneic stem cell transplantation can result in the induction of potent antitumor immunity (38). However, although theoretically attractive, there is not yet extensive data in humans to demonstrate the efficacy of a combined vaccine and adoptive T cell transfer approach in the autologous setting.…”

Keratinocyte growth factor enhances DNA plasmid tumor vaccine responses after murine allogeneic bone marrow transplantation

“…We and others have reported on the utility of tumor vaccines as a means of enhancing the graft-versus-tumor effect in allo-BMT recipients, [14][15][16][17][18][19][20][21][22] and this strategy also was reported in a clinical trial. 23 We previously showed in murine models that DNA tumor vaccination after allo-BMT is quite effective, capable of producing antitumor T-cell responses and rejection of subsequent tumor challenges and markedly improving the long-term survival of tumor-bearing mice in treatment models. 14 Strategies to enhance CD8 ϩ T-cell responses to vaccination have not focused on agents with a predominant effect on thymopoiesis.…”

Donor immunization with WT1 peptide augments antileukemic activity after MHC-matched bone marrow transplantation

“…This approach may have value for clinical translation which is currently in development with early phase trials for acute myeloid leukemia and multiple myeloma. 40,41 …”