When it comes to competitors to Bellicum’s “suicide switch” technology the group’s chief executive, Tom Farrell, doesn't pull his punches. “They’re not switches,” he says of Juno and Cellectis’s rival approaches.
Then again, he would say that, since the switch – a safety net against the notorious side effects of T-cell therapies – is one of his group’s main selling points. It is employed in Bellicum’s lead project, BPX-501, whose use in the transplant setting is a key focus at the upcoming ASH conference and could provide a blueprint for follow-up CAR-T and T-cell receptor projects in oncology.
There is one, admittedly extreme, school of thought that says no CAR-T project will gain approval without an inbuilt switch to ablate the T cells quickly in an emergency. Bellicum’s employs gene-engineered proteins that, upon the administration of the small moledule rimiducid, dimerise and trigger cell destruction.
Meanwhile, Juno and Cellectis incorporate expression of cell surface proteins that can be triggered with Erbitux and Rituxan respectively to cause T-cell ablation. The difference? These kill via antibody-dependent cell-mediated cytotoxicity – a process that causes inflammation – while Bellicum’s triggers clean apoptosis.
For the killer blow Mr Farrell cites a Juno study presented at ASH last year, in which investigators from Fred Hutchinson reported deaths. “The question was asked, did you give Erbitux (to reverse the side effects)?” Mr Farrell tells EP Vantage. “The response was, ‘No, we were afraid we would make the situation worse.’”
The data Bellicum is presenting at ASH concern BPX-501, which in many ways can be seen as a trial run for the entire technology. The chief exec calls it a “platform ... for the ability to control the cell, in the patient, with a small-molecule drug”.
BPX-501 is in effect an allogeneic stem cell transplantation procedure, designed to counteract physicians’ reluctance to transplant in some serious conditions on account of the concomitant risk of graft-versus-host disease (GvHD) and immune system suppression.
It involves the removal of alpha/beta T cells, which drive GvHD, followed two weeks later by an infusion of BPX-501 engineered cells to improve immune reconstitution (with the in-built suicide safety switch). The ASH abstract details 15 patients with various non-malignant conditions – including four with beta-thalassaemia – who have been “cured of their underlying disease”.
Of course it is hardly news that a stem cell transplant can cure beta-thalassaemia; rather, the relevance is in doing so without causing GvHD. Then there is the safety net provided by the suicide switch, says Mr Farrell: “A transplanter is willing to tolerate some level of GvHD, provided they have the comfort that there is a switch they can deploy if it gets worse.”
Still, the switch was not deployed in the latest study. That proof of concept came in an earlier, academic trial conducted at Baylor College of Medicine, in which the suicide switch was activated in eight of 22 transplant patients.
However, the chief exec stresses that that first-in-human study had a very stringent FDA-imposed threshold of grade 1 GvHD for triggering the switch; Bellicum’s current study has a higher threshold of grade 3/4 GvHD. “We don’t want to administer rimiducid unless the physician thinks it’s essential to do so.”
Neither was there a need to triggger Cellectis's CD20-based ablation technology in the recent case report at Great Ormond Street Hospital, though the UCART19 construct did include it (A bittersweet outcome for Cellectis, November 19, 2015).
Either way, Bellicum's 53-patient study will be keenly watched at ASH, especially as Mr Farrell revealed that it could detail around 25 more patients than included in the abstract.
The same suicide switch is being employed in Bellicum’s autologous engineered T-cell receptor project BPX-701, for whose use in uveal melanoma and sarcoma an IND is to be filed next month.
At the same time an IND will be filed for BPX-601, a CAR-T against PCSA for pancreatic cancer – “a swing for the fences” – which includes not an off but an on-switch. This comprises a first-generation CAR construct plus a separate signalling domain triggered with rimiducid using the same dimerization technology as in BPX-501, this time to activate the cells.
But are these switches really efficient? “With BPX-501 even after you give rimiducid there’s a population of T cells that remains and re-expands,” admits Mr Farrell, but he points to animal models suggesting that remaining cells continue to provide an antitumour benefit but do not appear to cause toxicity.
As to whether you have to have the ability to get rid of every last T cell, “that’s a question we fundamentally have to answer in the clinic”.