Transforming transplantation

Listen to Professor David Sachs explain the clinical problems facing the field of transplantation, and how our lead candidate Siplizumab can help improve the lives of transplant patients.

Rejection after organ transplantation is both debilitating and potentially life-threatening. The incidence of acute allograft rejection is highest in the first 3-6 months post-transplantation, but can occur throughout the course of the transplant. Large multicenter trials have demonstrated that it is exceedingly rare for patients to successfully stop chronic immunosuppression post-transplant. In a study surveing 218 913 organ transplant recipients, 61 patients were found to be completely free of chronic immunosuppression (Massart et al, 2016), giving a frequency of only 0.028%. These rare patients nevertheless demonstrated excellent long-term outcome, superior to patients on chronic immunosuppression. Similar observations have led to the initiation of randomized placebo-controlled trials attempting to wean transplant patients from chronic immunosuppression. Disappointingly, such studies have been terminated prematurely because all patients assigned to the placebo group developed various signs of rejection (Dugast et al, 2016) and had to be reintroduced on full-dose chronic immunosuppression (Figure 1).

Thus, with the currently available immunosuppressive regimens acute rejection is an underlying threat throughout the course of a transplant. Patients must therefore be maintained on life-long conventional immunosuppression with concomitant risks of cancer (Marcen et al, 2009), infections (Alangaden et al, 2006), cardiovascular disease (Lentine et al, 2005), diabetes (Marchetti et al, 2000) and other metabolic derangements. Patients experiencing acute rejection must be admitted to a University hospital and undergo invasive procedures such as transplant biopsies. This can lead to prolonged periods of hospitalization.

In addition, treating recipients of solid organs with life-long immunosuppression fails to protect the transplant from a chronic immune response, which leads to suboptimal long-term results. Only about 50% of patients retain a functional organ transplant after 10 years (Figure 2), most of which are lost due to chronic rejection, cancer, infection and cardiovascular events, which in turn are direct consequences of the currently used immunosuppressive drugs (Matas et al, 2008).

The treatment developed at ITBMed has the potential to provide substantial improvements in the treatment of transplant patients (read more under Siplizumab).

Figure 1. Flow diagram showing that transplant patients on conventional immunosuppression can not be withdrawn from treatment.

Adapted from Dugast et al, 2016.

Figure 2. Graft survival after organ transplantation. Only about 50% of patients retain a functioning organ 10 years after transplantation.

Adapted from Collaborative Transplant Study (all transplants, year 1985-2011).