CAR-T: the next generation

The next generation of CAR-T therapies is already emerging.

The hype over CAR-T therapy has reached epic proportions, but companies in the space are already looking beyond current products to next-generation technologies addressing new tumour types or promising fewer side effects.

Two deals yesterday – Gilead’s purchase of the 87.8% of Cell Design Labs that it does not already own, and Bluebird Bio’s licensing of TC BioPharm’s gamma delta CAR-T cells – could have other smaller players with similar approaches wondering if they are next.

The new black

One such group, which came out of stealth mode this week with a $49.5m series A round, is Obsidian Therapeutics, led by the serial biotech entrepreneur and Atlas Venture partner Michael Gilman.

According to the company it has developed technology that allows “exquisite control” over CAR-T therapies, which could improve safety and efficacy. It could also expand their use into solid tumours, where first-generation therapy has so far fallen short.

Safety is a well-known issue with CAR-T, with life-threatening cytokine release syndrome and neurotoxicity developing in some patients – indeed, deaths are not uncommon in CAR-T trials (Spotlight – Putting a number on CAR-T deaths, June 26, 2017). 

Obsidian’s technology is based around so-called destabilising domains, protein domains that can be incorporated into cell and gene therapies and which keep them “switched off” unless activated by a small-molecule drug. The system has been described as a volume knob for CAR-T.

However the group, which appears to be at the preclinical stage, still has a way to go to prove that its tech does what it says.

Gilead Notches another deal

Compared with the $12bn it shelled out for Kite, Gilead is paying a lot less for Cell Design, but $175m up front and up to $322m in milestones is still a substantial amount for an early-stage company. The deal gives Gilead complete control of Cell Design for $497m, as it already owned the 12.2% stake that Kite had bought.

That stake had cost Kite $6m, over 10 times less than the exit valuation Cell Design will have achieved if all the milestones are triggered.

Kite also paid Cell Design $2m up front when it licensed exclusive rights to the latter’s Throttle technology in acute myeloid leukaemia in June 2016. Throttle sounds similar to Obsidian’s approach in that it is described as an “on/off switch” that modulates CAR-T activity using small molecules.

Cell Design’s other tech, synNotch, can be used to create a “programmable” immune cell, in which a CAR construct is not actually expressed on the surface until a relevant antigen is present. The company says that one application for the technology is creating CAR-T cells that require the presence of two antigens for activation, which could better discriminate between healthy and cancerous tissue. synNotch was discovered at UCSF by Dr Wendell Lim, who is one of Cell Design’s founders.

Dual antigen approaches as a general concept are not new, with Juno and Autolous both working on something similar (Interview – Next from Autolus, cracking tolerance and solid tumours, September 27, 2017). 

The Cell Design deal was taken by Stifel analysts as a positive sign for another Kite collaborator, Alpine Immune Sciences, which is developing transmembrane immunomodulatory proteins (TIPs) to enhance cell therapies.

Gamma delta

Meanwhile, Bluebird is making a bet in a hot new area, gamma delta T cells, using these to express CAR constructs,  through a licensing deal with the UK company TC Biopharm worth $16m up front.

TC’s ImmuniCAR platform is also designed to create T cells that differentiate healthy from diseased tissue, and could also have utility in solid tumours, the company believes. It involves modifying gamma delta T cells, which have a role in immunity and express a distinctive T-cell receptor, to also express a chimeric antigen receptor. Both of these would need to be activated to trigger a response.

The technology is still at the preclinical stage. TC is responsible for development of all targets up to phase I/II, then Bluebird has an exclusive option to take on further clinical development and commercialise any products that make it to market.

The gamma delta field has been getting crowded lately: others in the space include the Puretech Health subsidiary Nybo Therapeutics, Gadeta, Gammadelta Therapeutics, Incysus, Lymphact and Medinet. However, with the exact role of gamma delta cells still not well understood, the field seems likely to thin out at some point.

Both of this week’s deals represent early-stage bets, so might come to naught. But they show that gaining a potential new edge is becoming ever more important to CAR-T players.

To contact the writer of this story email Madeleine Armstrong in London at madeleinea@epvantage.com or follow @ByMadeleineA on Twitter

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