A CAR-T suicide switch for hire

When Bellicum Pharmaceuticals raised $161m in a flotation on the back of the CAR-T craze its selling point was a clever technology dubbed the “suicide switch”, designed to provide a safety net against T-cell therapies’ notorious side effects.

So it might come as a surprise that the group’s latest plan is to offer its competitors licences to this very technology. Of course, this is in no way a sign of Bellicum giving up on the suicide switch; rather the company seems keen to monetise it in areas where it believes it either has no interest or no way to compete.

It basically boils down to targets. On a call yesterday Bellicum’s chief executive, Tom Farrell, said the company would consider licensing its CaspaCIDe suicide switch on an antigen-by-antigen basis to third parties “for antigen targets outside our wheelhouse”.

At present Bellicum’s CAR-T (chimaeric antigen receptor T-cell) assets are directed against the widely targeted CD19 antigen, as well as prostate stem cell antigen (PSCA). Already Bellicum has had many discussions with interested players, Mr Farrell revealed.

Essential component?

Suicide switches are seen by some as an essential component of a successful CAR-T therapy, given side effects like neurotoxicity and cytokine release syndrome that have hit some of the players, most notably Juno Therapeutics.

The idea behind CaspaCIDe is to engineer a gene into the target T-cell, causing it to express the human caspase 9 protein fused to a drug-binding domain. This intracellular protein can be triggered by the infusion of a specific small molecule, rimiducid (which Bellicum licensed from Ariad Pharmaceuticals), prompting dimerisation of the caspase 9 proteins and cellular destruction.

The most advanced project to include this off switch is Bellicum’s lead asset, the phase I haematopoietic stem cell therapy BPX-501, which uses it to control graft-versus-host disease. BPX-401, an anti-CD19 CAR-T project that also incorporates it, will not enter the clinic until 2016, while BPX-701, a T-cell receptor therapy for solid tumours, could enter phase I this year.

But if Bellicum really is the pioneer in controllable T-cell therapies why should it want to give the competition a slice of the action? One answer might be that the group has realised that it no longer has a monopoly in this field, and might as well generate cash from non-core targets – assuming a deal can be structured this way.

Indeed, Juno itself has a suicide switch of its own in early development. This consists of inserting a gene that causes the expression of an inactive truncated EGF receptor, in addition to the CAR; the receptor can be activated by a commercially available antibody like Erbitux, initiating rapid killing of the T-cells.

The recently launched private UK company Autolus is also known to be working on up and down control of T-cell activity (Interview – UK CAR-T player enters in stealth mode, January 23, 2015). France’s Cellectis, a pioneer of allogeneic CAR-T therapy, has mentioned expression of RQR8 as a suicide mechanism in early work.

“On” switches

For now, a separate application of Bellicum’s technology – which uses rimiducid as an activation rather than deactivation mechanism – is to remain in-house, said Mr Farrell. Bellicum projects using this on-switch approach comprise the clinical-stage dendritic cell vaccine BPX-201, and BPX-601, a CAR-T therapy for PSCA-overexpressing solid tumours in preclinical trials.

The chief exec said Bellicum was also investigating “additional antigen targets, novel molecular switches and approaches to off-the-shelf delivery of cellular immunotherapies”. This last point is an unusual development, the group until now having focused exclusively on autologous therapies.

Still, while Bellicum has blazed the trail in one particular aspect of immunotherapy, the unavoidable conclusion looking at its plans is just how early-stage its pipeline is. Moving to strike non-exclusive technology licences might merely be an acceptance of this fact.

EP Vantage has published a broad overview of the current opportunities and risks in the CAR-T space. A free copy of the report is available by download.

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobPlieth on Twitter