Induction of potent NK cell-dependent anti-myeloma cytotoxic T cells in response to combined mapatumumab and bortezomib.

There is increasing evidence that some cancer therapies can promote tumor immunogenicity to boost the endogenous antitumor immune response. In this study, we used the novel combination of agonistic anti-TRAIL-R1 antibody (mapatumumab, Mapa) with low dose bortezomib (LDB) for this purpose. The combination induced profound myeloma cell apoptosis, greatly enhanced the uptake of myeloma cell apoptotic bodies by dendritic cell (DC) and induced anti-myeloma cytotoxicity by both CD8+ T cells and NK cells. Cytotoxic lymphocyte expansion was detected within 24 h of commencing therapy and was maximized when myeloma-pulsed DC were co-treated with low dose bortezomib and mapatumumab (LDB+Mapa) in the presence of NK cells. This study shows that Mapa has two distinct but connected modes of action against multiple myeloma (MM). First, when combined with LDB, Mapa produced powerful myeloma cell apoptosis; secondly, it promoted DC priming and an NK cell-mediated expansion of anti-myeloma cytotoxic lymphocyte (CTL). Overall, this study indicates that Mapa can be used to drive potent anti-MM immune responses.

Drug-mediated and cellular immunotherapy in multiple myeloma.

Multiple myeloma is an immunologically relevant disease, which subverts and suppresses immunity, but that may also be amenable to immunological control. Novel drug and cell-based therapies provide an opportunity for the design of antimyeloma immunotherapy. Reversing the immunosuppression associated myeloma remains a substantial challenge. The minimal residual disease setting achieved by autologous stem cell transplant or highly efficacious induction therapy may reverse this immunoparesis and provide a setting for induction of antimyeloma T-cell responses. Adoptive cytotoxic T-lymphocyte/NK therapy and comprehensive treatment with immunomodulatory drug therapy represent means by which antimyeloma immune responses may be promoted. In addition, apoptosis-inducing therapies may prime endogenous antigen presentation via immunogenic cell death, which again may be enhanced by the addition of immunomodulatory drug therapy.