Ash preview – a low-key damp squib for cell therapies

Adoptive cell therapy stocks largely managed to escape the market carnage wrought by disclosure of the Ash meeting abstracts yesterday. But their mediocre performance shows just what a damp squib Ash promises to be, at least for the leading CAR-T players, just when they are approaching regulatory filing.

True, incremental progress is being made by numerous early projects targeting novel antigens, but investors will have to search high and wide to find these. As it stands the most closely watched could be an update on Juno’s JCAR018, and two novel constructs from Novartis and Kite designed to improve cell persistence.

Some investors will still be disappointed: the NCI’s Dr Terry Fry, who is running the JCAR018 study, appears to have treated no more than the nine patients he had outlined at the AACR meeting in April (The next CAR-T target generates promise and caution, April 25, 2016).

The aim is to use JCAR018, targeting CD22, in patients who have relapsed on a CD19-directed construct, but the Ash abstract reveals an underwhelming 44% complete remission rate. However, lack of severe neurotoxicity, in contrast to most of the leading CAR-T projects, remains an intriguing feature of JCAR018.

Human CARs

While an anti-CD22 CAR can be used to tackle relapse by antigen escape, relapse due to lack of cell persistence might be avoided by using a CAR with a human binding domain, rather than the murine ones employed by all the leading players today. To this end Novartis is developing the humanised CTL119, and Kite and Juno are in early trials with fully human constructs, huCD19 and JCAR021 respectively.

At Ash the University of Pennsylvania’s Dr Shannon Maude will present an update on CTL119, now involving 30 ALL patients – up from the 10 she detailed at Asco and six at Ash 2015. The abstract says 87% of these patients had complete remissions at one month.

Kite, meanwhile, is touting the first ever clinical data with huCD19, showing responses albeit of very short duration. Curiously, though Kite announced the exercise of an exclusive licence to huCD19 in July, in September the US Federal Register revealed that the NCI was considering granting a licence to it to Sangamo.

Yesterday, with several Ash stocks nursing double-digit losses, Kite and Juno fell 5%. Ziopharm was off 9% – the group only has preclinical updates to its Sleeping Beauty gene transfer system – Cellectis and Celyad lost 1%, and Bellicum remained flat.

Celyad vs Cellectis

Cellectis was the early star of Ash 2015, surprising investors with a case study of the first human treated with the allogeneic CAR UCART19. There is no such luck this year. Instead, its spat with Celyad over a genome-editing patent got more acrimonious, with Celyad yesterday accusing its chief executive, Andre Choulika, of “false and misleading information”.

Celyad has its own problem, though, and an Ash abstract reveals that its NKG2D-expressing T cells failed to persist beyond a week in the first 11 AML/myelodysplastic syndromes patients treated. Cellectis, meanwhile, reveals that a BCMA-targeting project, UCART-BCMA, is part of its multi-target alliance with Pfizer.

BCMA is an increasingly important target in multiple myeloma, though there is no update from Dr James Kochenderfer on an NCI trial of an anti-BCMA CAR that could have read across to Bluebird’s own bb2121, whose first clinical data are due next year. A Novartis/Penn asset against this target is proving unspectacular.

Much more important for Novartis investors will be an update to the pivotal Eliana trial of CTL019, which could be filed for ALL next year; the abstract shows an 83% complete remission rate, slightly below the earlier single-centre study, though this is only at 28 days, and of course lack of persistence will weigh heavy.

With Kite still gunning to beat Novartis to market with KTE-C19 investors will be keen to see more data from the Zuma-1 trial, but the six-month point will not be reached until January, so any impromptu update at Ash will surely relate only to the three-month cut toplined in September.

It is possible that the Zuma-1 abstract and many others are mere placeholders for more up-to-date results at Ash itself, and this is precisely the hope to which cell therapy followers will have to cling.

Selected cell therapy presentations at Ash 2016
Project Company Date Abstract Note
CTL019 Novartis 3 Dec 221 Pivotal Eliana study; 83% CR at 28 days, 3 manu failures
CTL119 Novartis 3 Dec 217 26 CRs in 30 ALL pts
JCAR014 Juno 3 Dec 56 Combo with ibrutinib in CLL
Anti-BCMA CAR Poseida Therapeutics 3 Dec 2127 Based on centyrins scaffold, preclinical
CTL019 Novartis 4 Dec 281 "CAR-B cells", relapse via accidental CAR transduction into an ALL cell
UCART-BCMA Cellectis/Pfizer 4 Dec 381 Fully human ScFv, RQR8 switch, preclinical
Dual anti-BCMA/TACI CAR Autolus 4 Dec 379 CD52 knockout; preclinical design
NY-ESO-1 CAR Ziopharm 4 Dec 3366 Sleeping Beauty transfer, preclinical
KTE-C19 Kite 4 Dec 2803 Preliminary Zuma-3 & 4 data
KTE-C19 Kite 5 Dec 998 Zuma-1 update
huCAR19 Kite 5 Dec 999 Short-duration responses in 4/6 lymphoma pts
JCAR017 Juno 5 Dec 4192 Incremental clinical data in lymphoma
JCAR018 Juno 5 Dec 650 4 CRs in 9 ALL pts
BPX-501 Bellicum 3 Dec 72 2 cases of GvHD resolved on triggering iC9 suicide switch
CART-BCMA Novartis 5 Dec 1147 1 CR, 1 PR in 6 multiple myeloma pts
NKR-2 Celyad 5 Dec 4052 T cells failed to persist for >1 week
CD33 CAR Ziopharm 5 Dec 4058 Lentivirally transduced, preclinical AML data

To contact the writer of this story email Jacob Plieth in London at [email protected] or follow @JacobPlieth on Twitter. For live updates from the ASH meeting in San Diego, on December 2-6, follow @JacobPlieth or @ByJonGardner on Twitter.

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