Hematologic malignancies are conditions where the bone marrow is damaged and the body stops to produce normal blood cells, and this calls for a need for allogenic hematopoetic cell transplant (allo-HCT). It is a curative used wherein stem cells from a donor, whose immune system is closely matched to the recipient are transplanted so that body starts producing blood normally. Graft-versus-host disease (GVHD) still remains a main challenge to allo-HCT, reasons being an increased amount of CD3⁺ T lymphocytes in the donor allograft, which causes a delay in the engraftment time, making way for increased risk for disease relapse and opportunistic infections.
A team of health researchers from the University of Florida by teams led by Grant McFadden and Christopher R. Cogle have discovered an ex vivo virtherapy with the oncolytic poxvirus, myxoma virus (MYXV), a rabbit virus which selectively targets malignant human hematopoietic cells like those of myeloid leukaemia and multiple myeloma and spares the normal hematopoietic stem cells and progenitor cells. They serendipitously discovered that in mice which received human HCT xenograft treated ex vivo with MYXV developed no GVHD, lived longer and accepted the engraftment. In essence, they confirmed that this rabbit virus delivers a one-two punch, killing cancer cells and completely eliminates the complications of a bone marrow transplant.
With the confirmation that MYXV virus lacks the ability to bind or infect normal human hematopoietic stem cells, this is the first study of its kind to confirm MYXV binds with unstimulated CD3⁺ T lymphocytes but T-cell activation is required to initiate virus infection and this can be delivered to cancer cells. In addition to efficiently infecting stimulated human T lymphocytes from all the donors, MYXV impaired T-cell functionality by reducing the T-cell proliferation and down regulating pathways that are involved in GVHD. Through the course of the study, they stumbled upon the ability of MYXV to infect only stimulated T cells thereby showing full replication and then be transferred to susceptible target human cancer cells mediating oncolytic effects targeting human myeloma cells.
In a nutshell, the study proves that ex vivo therapy regimen with MYXV has the potential arm to the resting T cells in the donor allograft, which is triggered to the replication cycle only after the T cells encounter efficient T-cell proliferation. If the host cells are non-cancerous, the oncolytic virus suppresses T-cell proliferation and if cancerous, the virus is transferred from the T lymphocytes, target and kill cancer cells. This new graft-virus malignancy (GVM) by the donor transplant now becomes a virus-versus-malignancy (VVM). This approach seems to be a godsend in terms of generating an in situ vaccination via the T-cell mediated delivery against tumor antigens.
The research was supported by grants of $1.5 million each from the Florida Bankhead-Coley Cancer Research Program and the National Institutes of Health/National Cancer Institute and additionally by the Gatorade trust.
Source: University of Florida.
The original paper can be accessed here.