Unexpected revelation of data from a single patient treated with Cellectis’s allogeneic CAR-T construct allowed the French company to steal the early limelight in yesterday’s unveiling of abstracts for the ASH conference in Orlando.
But the relatively muted reaction – Cellectis ADRs closed up 18% – might suggest that lessons are being learnt about placing undue reliance on tiny studies. A case in point is Bluebird Bio, whose stock had surged 62% on four-patient beta thalassaemia data at last year’s ASH; the unveiling of an update to this trial in Orlando marked Bluebird, off 22% yesterday, as the first big loser of ASH.
Not that Bluebird’s latest data cut, from the Northstar trial of its Lentiglobin gene therapy, is bad – far from it. But it comes down to baseline expectations; after the company’s market cap breached $7bn, and with some in the market touting that it had a “cure” on its hands, things could only really go downhill.
The group’s ASH presentation details four patients who have a less severe form of beta-thalassaemia, in whom Lentiglobin has prompted production of beta-globin, and who remain transfusion-free for over 90 days. So far so good (Bluebird sings sweet music to the ears of investors, December 9, 2014).
But the problem is with three other patients, with the beta-0/beta-0 form of the condition in which almost no beta-globin is produced: two have received a transfusion and one remains transfusion-dependent. The market must now dial back any expectation of a cure for all beta-thalassaemia forms.
Cellectis investors enjoyed a surprise of the opposite kind, given that the company had never even disclosed that its lead, genome-edited, allogeneic CAR-T project UCART19 had been tested outside a preclinical setting.
But according to an ASH abstract doctors at UCL and Great Ormond Street Hospital administered UCART19 to an 11-month-old child with high-risk, progressed acute lymphoblastic leukaemia. The key was that the scientists were unable to generate autologous CAR-T cells from the child, so gave the off-the-shelf UCART19 as a last resort on a compassionate-use basis.
This “induced molecular remission where all other treatments had failed”, the abstract states. Full data will be one of the hottest presentations at ASH, and investors will want more reassurance about the relatively short follow-up period cited in the abstract.
It is puzzling that Cellectis never disclosed that the compassionate use was being pursued, and the first glimmer of this emerged in a sellside note from Oppenheimer this week. UCART19 will not enter formal clinical trials until next year.
Clearly, however, since the ASH data represent the first human use of Cellectis's UCART19, if they translate into positive findings from larger studies they could pose a significant threat to autologous CAR-Ts, whose application presents practical problems that will drive up their cost and might limit real-world use.
Another "allogeneic" CAR-T project being profiled at ASH is the NIH's CD19-directed construct, in a study in 20 patients with various B-cell malignancies. The ASH abstract reports six complete and two partial remissions.
The NCI collaborates with Kite under a co-operative R&D agreement, but Kite appears to have no involvement in, or rights over, this CD19 CAR-T project. Still, this is not a true off-the-shelf approach since the T cells are derived from the patients' bone marrow donors.
In tandem with the Cellectis data the leading autologous CAR-T player, Juno Therapeutics, fell 7%, while Kite Pharma was off 2%. Both will of course feature at ASH, with the phase I part of Kite’s Zuma-1 study of KTE-C19 in non-Hodgkin’s lymphoma being key; Zuma-1 recently started its phase II, registrational portion.
|Selected ASH presentations|
|Lentiglobin||Bluebird Bio||201||Update of Northstar trial; 4/7 patients remain transfusion-free.|
|Luspatercept||Acceleron/Celgene||752||Increased Hb levels in transfusion-free beta-thalassemia patients.|
|GBT440||Global Blood Therapeutics||542||Additional data in sickle cell disease patients.|
|UCART19||Cellectis||2046||First human case study of this allogeneic anti-CD19 CAR-T.|
|Bone marrow donor-derived CD19 CAR-T||NCI||99||8/20 remissions in B-cell malignancies, including 6 CRs.|
|CTL019||Novartis||681||Further data from ongoing paediatric ALL trial.|
|KTE-C19||Kite Pharma||3991||Phase I portion of Zuma-1 trial; possible advance on 28 July cutoff in abstarct.|
|BPX-501||Bellicum||1931||Safety and tolerability, possible early signs of CaspaCIDe suicide switch.|
|JCAR015||Juno||2533||Multicentre trial of children and young adults with relapsed CD19+ B-ALL.|
|LG740||Juno/Opus Bio||1324||Clinical activity of anti-CD22 CAR-T in CD19-negative relapses.|
|CD34-selected allo transplants + WT1-specific T cells||Atara||98||Initial results from pts with plasma cell leukemia or r/rMM.|
|Dendritic cell vaccine||Medigene||3805||Investigator-sponsored trial showing feasibility in AML.|
A key focus for all the CAR-T and other cell therapy studies will be how to deal with relapses, as well as with adverse events, in particular neurotoxicity and cytokine release syndrome.
Cellectis, Juno and Bellicum are all working on “suicide switch” approaches to mitigate toxicity through the ability to ablate all the CAR-T cells, though this work is extremely early. For Bellicum phase I/II data of BPX-501, a T-cell therapy for stem cell transplantation, will be important at ASH.
While BPX-501 is not a CAR-T construct, it does use Bellicum’s CaspaCIDe suicide switch. As far as relapsing patients go, investors will be looking for strategies to treat those that relapse owing to loss of the CD19 antigen, since these clearly cannot be retreated with a CD19 CAR-T.
Juno, for instance, has an abstract on treating CD19-negative relapses with a CD22 CAR-T that it licensed from Opus Bio last year, while Cellectis is conducting early work on a CD123-targeting construct as well bispecific CAR-Ts.
Late-breaking abstracts will be unveiled on November 16, providing another inflection point for biotech stocks before the actual meeting kicks off on December 4.