A New Cellular Immunotherapy for the Treatment of Multiple Myeloma without Development of Graft-Versus-Host Disease

Sofi Yado, Chemical Engineering , Ariel University, Ariel, Israel
Galia Luboshits, Chemical Engineering , Ariel University, Ariel, Israel
Michael A. Firer, Chemical Engineering , Ariel University, Ariel, Israel
Reuven Or, 2cancer Immunotherapy & Immunobiology Research Center, Hadassah University Hospital, Jerusalem , Israel

Multiple myeloma (MM) is a malignant plasma cell disorder that accounts for approximately 10% of all hematological cancers. Despite recent advances, long-term survival is rare after autologous bone marrow transplantation (auto-BMT) and/or treatment with recently introduced anti-myeloma agents, and disease recurs in virtually all patients. From the other side, allogeneic bone marrow transplantation (allo-BMT) is an effective treatment that can provide partial or complete remission for patients with MM. The therapeutic potential of allo-BMT is attributed to the "graft-versus-myeloma" (GvM) effect that aims to destroy residual tumor cells that survived an induction protocol of chemotherapy/radiotherapy and to maintain immune surveillance to prevent relapse. However, allo-BMT remains a controversial treatment, since the donor T cells that mediate the GvM effect are also the source of the cells that react to other tissue alloantigens and induce graft versus-host disease (GvHD), a major cause of morbidity and mortality in allo-BMT recipients. Nonetheless, allo-BMT remains the only potentially curable treatment for MM. Recent TCR Vβ CDR3-size spectratype analyses in an animal model of MM identified T cells subfamilies involved in the anti-host and anti-tumor reactivity. Based on these results, we tested the potential of integrating auto-BMT with a donor lymphocyte infusion (DLI) composed only of anti-MM reactive Vβ 2, 3 and 8.3 T cell subfamilies. The results demonstrate that these T cell subsets are indeed involved in the generation of a GvM response in MM bearing mice and enhancement of survival. Importantly, this GvM response was not accompanied by the development of GvHD. Nonetheless, the GvM response was not sufficient to completely inhibit relapse. Next, we pre-stimulated donor T cells with MM cells in vitro in the presence of co-stimulatory factors and found that, our selective DLI protocol induced a vigorous and long-lasting GvM which translated into long-term survival in the complete absence of GvHD. Interestingly, we obtained almost a similar result by treating MM-beraing mice with repeat doses of naïve donor T cell subfamilies. The treated mice showed lower serum paraprotein levels and lower myeloma infiltration in bone marrow and spleen. Taken together, the results suggests that a transplantation protocol involving only tumor-reactive donor T cell subfamilies can be devised for MM patients that results in enhanced survival without symptoms of GvHD.