The driving interest in Bellicum revolves around its safety switch for use in hematologic stem cell transplants. It’s product, BPX-501, is a T-cell therapy containing a caspase-9 gene that can be activated by the compound rimiducid, leading to cell apoptosis.
BPX-501 is initially being positioned as an adjunct T-cell therapy for allogeneic HSCT. Stem cell transplants fall into two broad categories: allogeneic- from a donor, or autologous- from oneself. Allogeneic transplants often suffer from the lack of matching donors; in some cases, physicians resort to haplo HSCT where there is a partial mismatch in HLA genes, resulting in a higher risk of GVHD (Graft vs. Host Disease).
Bellicum believes BPX-501’s incorporated safety switch may lead to safer haplo allogeneic HSCT. In the case of a GVHD occurrence, infusion with rimiducid kills the vast majority of transplanted T-cells, helping to clear GVHD.
A 2011 NEJM POC study demonstrated BPX-501 acts in this exact way [Ref]: Five children received haploidentical transplants with BPX-501 cells. Four of the five developed early stage GVHD of the skin upon which the safety switch was activated. It was noted 90% of targeted T-cells were killed in about 30 minutes; GVHD cleared within 24-48 hours.
BPX-501 is now in formal Phase I/II clinical studies. Early results were presented at this weekend’s ASH convention. Interim data [Ref] have been presented by the company on the BP-004 study, focusing on 20 of 39 pediatric patients with non-malignant disease receiving BPX-501 add-back.
In this particular study, 7 instances of G1 or 2 GVHD were reported; none severe enough to require activation of the safety switch. The authors suggest a survival improvement with BPX-501 compared to “historical controls”. There was no transplant related mortality (TRM) in the 18 patients with at least 30 days of follow-up compared to 3 of 33 in the control study [I believe this is the referenced control.]
Additionally, it appears add-back of BPX-501 T-cells helped the immune system recover faster compared to historical control, leading to shorter hospital stays.
What Does This Mean?
These are interesting results but unfortunately do not provide any insight as to the benefit of the company’s key safety switch technology when it comes to non-malignant haploidentical transplants.
This study does contribute to the body of data that BPX-501 cells have a good safety profile. The problem is no Bellicum specific technology is required to conduct a similar trial to the one in progress with BPX-501.
One of the big advances in haplo HSCT and used by Bellicum is selective depletion of αβ⁺T-cells and CD19⁺B-cells from donor grafts to reduce immunogenicity and the potential for GVHD. It had already been known that full T-cell depletion produces such an effect. The idea is that by selectively removing the most immunogenic T-cells, remaining γδ T-cells can suppress and prevent infections while the patient’s immune system recovers.
The procedure has so improved haplo GVHD that some suggest it is now as safe as HLA-matched HSCT from unrelated donors. This change may vastly improve prospects for those requiring transplants but fail to find matches.
It appears a safety switch is no longer needed to make haplo HSCT safer. There remains a chance to contribute improvements. Because patients do not receive their full repertoire of T-cells in this new type of transplant, they may be more prone to deadly infections. If a full set of T-cells are added back post-transplant, there may be an immune boost and protective effect.
Results of this trial suggest add back of BPX-501 cells may have benefits over historical control procedures which did not use such a booster. There are some caveats. While no transplant related deaths occurred, the follow-up minimum period is only 30 days. In the referenced study, one patient died of infection at 120 and one at 116 days. Two-year overall survival was however high at 91%.
Bellicum is in a conundrum with T-cell add back for non-malignant diseases. Following transplants, patients can expect to live a fairly long life. Any treatment must carefully balance safety with efficacy. Assuming haplo HSCT can now achieve around 90% 2-year OS as found in the historical study, how much incremental benefit can add back with BPX-501 provide without bringing additional risk?
In non-malignant disease, the addition of a procedure that leads to an increase in Grade 3,4 GVHD would likely be unacceptable despite having a safety switch. The add back procedure must have a low occurrence of high grade GVHD yet improve survival. In this setting there will be little need for a BPX-501 safety net.
Simply put, non-malignant HSCT is the wrong indication for BPX-501. The company will need to prove its chops in the malignant setting where Grade 3 GVHD is welcome for its Graft vs. Leukemia effect. Risk tolerance is much higher. Testing the ability of BPX-501 T-cells to act as a booster in malignant disease post transplant will finally prove the effectiveness of its safety switch.
Disclosure: Author has no position