The patented Mirror EffectTM technology works by reversing the direction of the immunological flow of effects of allogeneic transplant procedures. Instead of the transplanted immune system (the graft) mediating the GVT and GVHD immune effects, the Mirror EffectTM “mirrors” or reverses the direction of the immune effects so that the effects remain intimately related but are mediated by the host rather than the graft. In this manner, the host immune system rejects the graft (a host vs. graft effect or “HVT”) which promotes the host immune system to attack the tumor (a host vs. tumor effect or “HVT”). The related HVT/HVG effects are the mirror of the GVT/GVH effects of allogeneic stem cell transplant.
Simply infusing allogeneic cells into a cancer patient does not result in any anti-tumor effects. Pre-clinical research demonstrated that anti-tumor effects can occur in either direction of graft -> host or host -> graft only in the context of first establishing a stable chimeric immune system. A chimeric immune system is where a donor immune system is engrafted and lives side by side with the immune system of a cancer patient. To create a chimeric immune system, it is required to first provide chemotherapy conditioning to a host in order to suppress the immune system from rejecting a donor (allogeneic) graft. After chemotherapy conditioning, foreign immune cells can engraft and create an immune system that is part-host and part-graft.
Under chimeric conditions, the infusion of more donor immune cells (called donor lymphocyte infusion or “DLI”) causes rejection of the remaining host immune cells. The rejection of the host immune cells serves as an adjuvant which supports the powerful GVT effect. However, the GVT effect occurs when the donor immune system kills normal cells causing GVHD.
Interestingly, it was discovered that this process could be reversed or ‘mirrored’. Under chimeric conditions the infusion of immune cells from the host (recipient lymphocyte infusion or “RLI”) causes the rejection of the engrafted donor immune system (see diagram). This host vs graft (HVG) rejection is the ‘mirror’ of the graft vs host (GVH) effect. However, unlike the lethal toxicity associated with GVH rejection, the ‘mirror’ host vs graft (HVG) rejection is not toxic. HVG rejection serves as an adjuvant to support a host vs tumor (HVT) effect which is as powerful as the GVT effect of allogeneic transplant but is intimately related to the non-toxic HVG rejection.
In the chimeric setting, the GVT effect occurs in the context of the graft attack on normal cells (GVHD). The HVT effect occurs in the context of the host rejecting the graft. Unlike GVHD, the HVG rejection is not toxic.
It was known that the human immune system is programmed to reject foreign agents. Prior to the discovery of the HVT effect, most researchers assumed that the GVT effect of allogeneic transplant occurred because the grafted immune system was foreign to the tumor and that GVHD occurred because the normal host cells of the patient were also foreign to the graft. If these effects only occurred if the immune system was foreign to the target tissue, then the mirror of the GVT effect, HVT, would not be observed. The HVT effect occurs when the tumor and the immune cells are from the same person.
Accordingly, the discovery of a HVT effect that is just as powerful as the GVT effect but occurs in the context of a non-toxic HVG rejection and occurred when the tumor and immune cells were from the same person created the basis for the development of the Mirror EffectTM technology portfolio of products.
However, the requirement for a chimeric immune system in order to observe non-toxic HVT effects limited the application of the Mirror Effect. A chimeric immune system required that patients first undergo a chemotherapy conditioning regimen, not for the purpose of killing tumors but instead for the purpose of suppressing the immune system in order that it not reject a donor immune system. Following chemotherapy conditioning, immune cells from a tissue matched donor are required. Tissue matching is required in order to further minimize the chance of the host immune system from rejecting the transplanted immune system. The best match is usually from a sibling. However, each sibling of a patient has only a 1 in 3 chance of being a donor match.
By analyzing the mechanism of the HVT effect, Immunovative scientists were able to reverse engineer the HVT mechanism into the design of a donor graft, called “AlloStim®”. This patented immune cell graft is derived from immune cells isolated from intentionally mis-matched healthy donors. AlloStim® is able to elicit the HVT effect in a normal patient, eliminating the need for chemotherapy conditioning and tissue matching