The Survivin Suppressant YM155 Overcomes Microenvironment-Mediated Immune Resistance In a Humanized Multiple Myeloma Mouse Model

Durable tumor regression can be achieved in Multiple Myeloma (MM) patients by immunotherapeutic approaches, such as allogeneic stem cell transplantation and donor lymphocyte infusion. However, the low rate of patients, who reach a sustained remission, impedes the success of this therapeutic approach. Currently, much emphasis is placed on the role of the tumor microenvironment in tumor cell immune escape. We previously described that different accessory cells of the microenvironment significantly inhibited the lysis of MM cell lines by T cells in a cell-cell contact dependent manner. Further analysis revealed that this immune escape could be attributed to the induction of a cell adhesion-mediated immune resistance (CAM-IR) of MM against T cell lysis in vitro. Further in vitro studies identified up-regulation of survivin in the MM cells as one of the potential mechanisms of immune resistance. Moreover, co-culture with YM155, a small molecule survivin suppressant, could abrogate accessory cell induced resistance in vitro.

We investigated the influence of a human bone marrow microenvironment on the anti tumor activity of T cell therapy in a human-mouse hybrid model (Groen et al. Blood 2012). Immune-deficient RAG2-/- γc-/- -mice were implanted subcutaneously either with uncoated scaffolds or scaffolds coated with human mesenchymal stromal cells (MSC), which generates a human bone marrow environment. Luciferase transduced MM cell line UM9 injected directly in both types of scaffolds grew into MM tumors and were treated with Myeloma reactive minor Histocompatibility antigen specific T cell clones. The T cells induced effective anti-myeloma responses against tumors developed in the uncoated scaffolds. In contrast, and consistent with the in vitro results, no anti-tumor effect was observed in the MSC coated scaffolds. Thus confirming in vivo a microenvironment induced resistance of MM cells to T cell kill. We next investigated if the resistance could be abrogated by combination therapy with T cells and YM155.To this end, mice with tumors in human MSC coated scaffolds were treated with T cells alone, YM155 alone, or the combination of both. YM155- nor T cell-monotherapy induced tumor regression on evaluation of tumor growth based on bioluminescent signal. Moreover, the combination of YM155 with T cells demonstrated a substantial anti-tumor effect.

YM155 treatment can sensitize myeloma cells to T cell mediated anti-tumor effects and more importantly can overcome microenvironment-mediated resistance of MM cells to T cell treatment. These findings support further development of CAM-IR modulating agents in combination with immune therapy.

Minnema:Janssen Cilag: Consultancy, Honoraria. Lokhorst:Genmab A/S: Consultancy, Research Funding; Celgene: Honoraria; Johnson-Cilag: Honoraria; Mudipharma: Honoraria.