Juno and Kite follow Novartis to make CAR-T human

The first human data presented at ASH with Novartis’s new humanised CAR-T project, CTL119, might have been extremely preliminary, but just weeks later there is evidence that other big players are following Novartis’s lead.

Yesterday saw the low-key announcement of two collaborations, involving Juno and Kite, to supplement these groups’ most advanced murine CAR-T projects with fully human constructs. The fact that many patients responding to CAR-T quickly relapse is a growing problem, and using a humanised or fully human antigen-binding region might help avoid immune system rejection of the treatment.

This was certainly the goal of Novartis’s academic collaborator, the Children’s Hospital of Philadelphia, which in an existing study of CTL019 in paediatric leukaemia is treating some relapsing patients with a new, humanised, CD19-targeting CAR – CTL119 (Therapy focus – How do you solve a problem like CAR-T relapse?, December 22, 2015).

Kite’s move involves signing a new co-operative R&D agreement with the NCI – specifically with Dr James Kochenderfer at the transplantation and immunology branch – to develop a fully human anti-CD19 CAR-T candidate for leukaemias and B-cell lymphomas.

This is a cautious initial step, giving Kite an early look at the NCI’s data, but as signing a CRADA implies no exclusive rights the group would have to negotiate a formal licence if it actually wanted to own the asset and data in question. Kite has a separate CRADA with the NCI’s surgery branch covering numerous CAR-T and engineered T-cell receptor projects.

However, Kite’s in-house CAR-T asset, KTE-C19, is licensed not from the NCI but from the Weizmann Institute’s Dr Zelig Eshhar. The company says the NCI’s fully human construct should start a phase I study this year; Dr Kochenderfer is to be primary investigator in a separate phase I trial of Bluebird Bio’s anti-BCMA CAR-T, bb2121.

Eureka!

Juno, meanwhile, has gone a step further, striking a full licence to a fully human binding region developed by a little-known private biotech, Eureka Therapeutics.

The initial focus of the deal is a MUC16 binder that will be used in conjunction with JCAR020, Juno’s anti-MUC16 CAR-T project, which recently entered a clinical trial in ovarian, fallopian tube and primary peritoneal cancers. JCAR020 is what Juno calls an “armored CAR”, additionally delivering the cytokine IL-12 to stimulate T-cell activation and recruitment.

This binding domain in question was developed by Eureka and Memorial Sloan Kettering Cancer Center, which is Juno’s partner on the CD19-directed JCAR015 project. A statement by Mark Frohlich, Juno’s head of development and portfolio strategy, cites the company’s continued pursuit of fully human binding domains, “with the goal of optimizing cell persistence”.

Juno previously said it had access to a library of fully human scFv domains, and separately its anti-CD22 CAR-T project, JCAR018, licensed from the NCI via Opus Bio, uses a fully human binding domain. Until now little had been known about Kite’s plans, though the group is known to have made a patent filing for a humanised CAR.

Of course, it has yet to be proved definitively that immune system rejection of the murine antigen-binding region on current CAR constructs is a major reason for poor cell persistence. That said, the deals show that several groups are taking the problem seriously and see humanised or fully human constructs as a solution.

To contact the writer of this story email Jacob Plieth in London at jacobp@epvantage.com or follow @JacobPlieth on Twitter

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