Safety and Preliminary GvHD Mitigation in First in Human Clinical Trial of Apograft in Match Related Stem Cell Transplantation (SCT)

Graft versus host disease (GvHD) is a major frequent adverse event (AE) and the primary cause of morbidity and mortality following allogeneic stem cell transplantation (ASCT).

Numerous attempts to reduce incidence and severity of GvHD using a variety of cell selection methods have been employed, but they all suffer from a risk/benefit trade-off where reduction of GvHD-causing cells leads to reduced engraftment and/or reduced graft vs. tumor (GvT) effect.

We have previously reported development of a new method for cell selection, which take advantage of cells' differential sensitivity to CD95 receptor mediated apoptosis. This technology enables the differential selection of transplant related immune-toxicity cells (e.g., TH1, TH17, terminally differentiated B cells and antigen presenting cells {APCs}) while maintaining stem and progenitor cells. Thus, selecting the right mix of cells may enable both GvHD reduction and maintenance of the graft's effectiveness.

Here we report results of our first in humans clinical trial using this functional cell selection technology (named ApoGraft). This study was an Open-Label Phase 1/2 Pilot, Staggered Four-Cohort Safety and Proof-of-Concept Study of ApoGraft in the Prevention of Acute Graft Versus Host Disease in Match related SCT (NCT02828878). The primary objective of the trial was to demonstrate safety and tolerability of ApoGraft in adult patients with hemato-oncology disorders. The key secondary objective was engraftment and prevention of acute GvHD.

Eleven patients were enrolled into this study in 4 sequential cohorts of 3 patients each, except for 2 patients in cohort 4. Enrolled subjects' transplant indications included AML (n=7), ALL (n=1), MDS (n=2) and biphenotypic acute leukemia (n=1). ApoGraft was manufactured ex-vivo from donor mobilized peripheral blood cells (MPBCs) collected via a single apheresis donation that was incubated for 2 hours with FasL protein (10, 25, 50 and 100 ng/ml per cohort), and washed before transplantation to the recipient. Patients were administered with a single ApoGraft treatment. The ApoGraft product median CD34+ yield was 72%, with a median of 4.3x10^6 CD34+ cells/Kg/patient. All patients received GVHD prophylaxis with short-course methotrexate and Cyclosporin A.

No AEs or serious AEs (SAEs) were recorded during stem cell infusion. Six months follow-up showed ApoGraft transplantation to be well tolerated with no related AEs or SAEs. Successful engraftment was observed in all subjects within the expected timeframe. Median time to neutrophils or platelets engraftment was 14 days. Lower incidence of grade 2-4 aGvHD was observed in Cohorts 3 and 4 (n=2) as compared to Cohorts 1 and 2 (n=5). None of the higher FasL dose Cohort 3 and Cohort 4 patients had grade 3 and 4 aGvHD compared to 3 patients in cohorts 1 and 2. Over 97% of bone marrow at 28 days post-transplant were of donor origin, indicating full donor chimerism, except for the two MDS patients; one had shown full donor chimerism, which was reduced at day 180 (55%). The other had a donor chimerism of 92% at day 28. None of the patients relapsed during the study period. Four of 6 patients in the 10 and 25 ng/ml cohorts had 7 episodes of CMV viremia, as compared with 1 episode in the 50ng/ml cohort and none in the 100ng/ml cohort. Ten patients survived and were progression-free by study day 180. One MDS patient died during the study due to study unrelated secondary graft failure.

Our results show evidence that the ApoGraft product was well tolerated at all FasL doses and demonstrated preliminary signs of GvHD mitigation when the higher ex-vivo doses of FasL (50 and 100 ng/ml) were used.