Safer and More Effective

The number of T cells (leukocytes) given in a DLI is limited by the risk of Graft-vs-Host Disease (GvHD), a potentially debilitating and sometimes fatal condition in which the donor T cells recognize the host as foreign, and mount an immunologic attack. GvHD can also develop as a result of T cells in the original stem cell transplant, if they are not removed. GvHD is characterized by damage to the liver, skin, mucosa and GI tract. It is widely recognized as the primary area of unmet medical need in stem cell transplantation.

To lower the risk of GvHD in a DLI, the number of T cells being infused must be minimized, and sometimes a sophisticated technique called allodepletion is used to eliminate graft T cells that will react with the host. However, the greater the number of T cells that are infused, the more protective the DLI is against infection, and the more effectively the foreign T cells attack vestigial cancer cells, thereby potentially lowering relapse rates. Providing T cells along with stem cells in a transplant may yield additional benefits, including more successful and rapid engraftment. Thus transplantation treatment decisions involve a win-lose trade-off between the risk of GvHD, the risk of infection, and the benefits of donor T Cells, including greater engraftment, immunity against viruses and fungi, and Graft-vs-Tumor effect.

With CaspaCIDe™ DLI, the infused T cells contain a GvHD “self destruct switch” that can be activated at any time by giving the patient an intravenous infusion of AP1903. AP1903 switches on the caspase signaling pathway inside each cell, leading to rapid apoptosis – programmed cell death. Thus the cells causing GvHD are eliminated, in a matter of minutes. Perhaps equally importantly, the T cells that are active at the time AP1903 is administered – which are the ones attacking the host – are preferentially eliminated, so the patient does not lose the benefit of the DLI. The remaining T cells that were not activated at the time can re-expand and reestablish immunity.

GvHD accounts for 12-13% of allogeneic transplantation-related deaths; infection, 16-19%; and relapse, 33-42%. By taking the risk of GvHD out of the equation, CaspaCIDe™ DLI not only eliminates treatment-related mortality (TRM) and morbidity attributable to GvHD, but it may also allow the use of higher T cell doses, providing greater and more rapid immunity against infection, and a more potent Graft-vs-Tumor effect, thereby also lowering TRM attributable to infection and relapse.

In addition to increasing the safety and efficacy of transplantation in well established indications such as leukemia and lymphoma, a substantial decline in transplantation risk could expand the use of this often curative therapy in non-cancer indications, such as autoimmune diseases. Stem cell transplantation is being used experimentally in lupus and multiple sclerosis, for example, where it can be curative, but high treatment-related mortality makes it unattractive in all but the most severe cases. CaspaCIDe™ DLI could thus enable transplantation to emerge as a potentially curative modality for autoimmune disease patients.