Myxoma virus suppresses proliferation of activated T lymphocytes yet permits oncolytic virus transfer to cancer cells

Abstract

Key Points MYXV binds human T lymphocytes but does not enter and infect T cells until after activation. MYXV-infected T lymphocytes proliferate less and secrete less inflammatory cytokines but deliver oncolytic virus to augment GVM.

Ex vivo virotherapy with myxoma virus does not impair hematopoietic stem and progenitor cells

“…However, >95% of all infections that initiate MYXV infection in human hematopoietic cells (i.e., cells that turn green after infection with vMyx-GFP) abort the virus replication cycle prior to the late stage of virus replication, and therefore cannot make progeny virus and are considered functionally nonpermissive for MYXV. Fresh mPBSCs showed slightly higher levels of MYXV infection initiation in differentiated cells like monocytes and NK cells, most likely due to manipulation-induced activation of some differentiated cells, as we have previously shown 15 . When considering our recent report of primary human T lymphocytes serving as transport vehicles for MYXV to target cancer cells 15 , the limited infection found in this study are interpreted as a potentially positive finding in assisting MYXV delivery to cancer cells post-transplant.…”

“…Fresh mPBSCs showed slightly higher levels of MYXV infection initiation in differentiated cells like monocytes and NK cells, most likely due to manipulation-induced activation of some differentiated cells, as we have previously shown 15 . When considering our recent report of primary human T lymphocytes serving as transport vehicles for MYXV to target cancer cells 15 , the limited infection found in this study are interpreted as a potentially positive finding in assisting MYXV delivery to cancer cells post-transplant.…”

“…Human peripheral blood mononuclear cells (PBMCs) were incubated with the vMyx-GFP/TrFP construct that expresses GFP at both early and late times of infection and TrFP at late times of infection only. In prior work, we have used this viral construct to determine the extent of permissiveness of various classes of test cells to MYXV 14,15 . Whereas, permissive cells show double positive fluorescence (GFP + TrFP + ) as a prelude to the synthesis of progeny virus that is indicative of a permissive infection, non-permissive cells may be revealed as either GFP + TrFP − or GFP − TrFP − .…”

“…Although our original intent with MYXV was to safely eliminate contaminating cancer cells from ASCT grafts 17,18 , our more recent work found that ex vivo MYXV treatment of allogeneic transplant grafts had the additional property of mitigating graft-versus-host disease 15,16 . Thus, we now predict that MYXV ex vivo virotherapy will be applicable to both auto- and allo-transplant methods.…”

Ex Vivo Oncolytic Virotherapy with Myxoma Virus Arms Multiple Allogeneic Bone Marrow Transplant Leukocytes to Enhance Graft versus Tumor

“…In addition to this, ex vivo virotherapy with MYXV also completely eliminated acute GVHD in this xenotransplanted mouse model by suppressing the subsequent expansion and infiltration of alloreactive human T lymphocytes into normal recipient tissues 16 . Recently, it was shown that normal human T cells can bind MYXV and can then co-traffic with these cells, but the virus infection is launched only after T cell activation 21 . Importantly, activated and/or infected T cells can subsequently donate the oncolytic MYXV to human MM cells via cell-cell contact 21 …”