One of the most cutting-edge approaches to treating B-cell malignancies – using chimaeric antigen receptor therapy (CART) – has also been one of the hardest to envisage becoming a commercial treatment.
Judging by a series of presentations at ASH, however, researchers are not deterred. Updated results of several studies conducted by Novartis suggest that, in some patients, responses have been striking, and toxicities might be controllable. Moreover, Novartis is no longer alone in this field, with two separate research groups also reporting early human data.
The approach is a neat one – at least conceptually – taking advantage of the fact that the CD19 protein is expressed almost universally on B-cells. Most groups are using a vector to modify a patient’s T-cells ex vivo, altering them so that they target CD19, before reinfusing the cells into the patient.
Deep molecular remission
The most advanced project is coded CTL019, in development through a partnership between Novartis and the University of Pennsylvania that had previously boasted of achieving durable responses. At ASH on Sunday the University’s Dr Michael Kalos said both previously reported complete responders in a CLL study were still in “deep molecular remission” three years after treatment.
CTL019 cells can still be detected in these responders, with ongoing B-cell aplasia, said Dr Kalos. A separate 22-patient paediatric ALL trial saw a remarkable 86% reporting complete responses; 14 of 19 complete responses are currently being maintained, with over three months’ duration.
Dr Kalos also provided mechanistic support for the approach, pointing out that all complete responders had achieved levels of bioengineered T-cells at up to 6% of a patient’s total T-cell count. Meanwhile, non-responders did not show any T-cell expansion, “for reasons we don’t understand”, said Dr Kalos.
The baton was picked up by the University of Pennsylvania’s Dr Stephan Grupp, who focused in on the five relapses in the paediatric ALL study. “One patient relapsed because her leukaemia cells no longer expressed the CD19 target,” he stated – a finding that also appears to back the way CART is expected to exert its effect.
Novartis and the University of Pennsylvania are not alone in developing the CART approach. The NCI is collaborating on its own CART project with the private company Kite Pharma, and the NCI’s Dr James Kochenderfer presented initial results from a phase I study in 15 patients with aggressive large-cell lymphomas and a variety of B-cell malignancies.
Seven of 13 evaluable patients achieved complete responses. Dr Kochenderfer highlighted one large-cell lymphoma patient who had had no fewer than 10 prior treatments, and was thus clearly chemo-refractory, with progressive disease. Despite this, a complete response was achieved, and is now being maintained nine months after treatment.
Meanwhile, the MD Anderson Cancer Center’s Dr Partow Kebriaei outlined a non-viral gene transfer approach using a transposon/transposase system called Sleeping Beauty to express “second-generation” CD19-specific T-cells. Four non-Hodgkin’s lymphoma patients treated with a high T-cell dose in a first-in-human study are in remission after three months, though a lower dose has proved less effective.
|Selected CART studies profiled at ASH|
|Study||Design||Data so far||Trial ID|
|University of Pennsylvania/Novartis|
|UPCC-04409||14 CLL patients||4 CRs, 4 PRs||NCT01029366|
|UPCC-04409||5 adult ALL pts||5 CRs||NCT01029366|
|UPCC‐03712||18 CLL pts||3 CRs, 4 PRs||NCT01747486|
|CHP‐959||22 paediatric ALL pts||19 CRs||NCT01626495|
|09-C-0082||40 pts with B-cell leukaemia or lymphoma||13 of 15 pts evaluable; 7 CRs, 5 PRs, 1 SD||NCT00924326|
|MD Anderson Cancer Center|
|2007-0635||25 pts with B-cell malignancies||4 NHL pts on higher dose in remission||NCT00968760|
|CR: complete response, PR: partial response, SD: stable disease|
However, Dr Kebriaei highlighted her group’s CART’s safety, saying that after five months no acute or liver toxicities had been seen. Toxicity remains one of CART’s concerns, with Dr Grupp noting cytokine release syndrome, and both the University of Pennsylvania and NCI groups talking of a “type of delirium” that persists in some patients for a couple of days before abating.
But the cytokine release problem – mainly involving IL-6 – now looks controllable thanks to administration of the anti-IL-6 receptor MAb Actemra. “This (drug) has been game-changing in controlling cytokine release,” said Dr Grupp.
Manufacturing, on the other hand, remains a perceived difficulty – unsurprising given the complexity of an autologous cell therapy. Novartis might have the upper hand here, having earlier bought a Dendreon plant to scale up.
The two groups working on lentiviral vector delivery reported a 10 to 14-day period of ex vivo modification before T-cell transfer back into the patient, and stressed that, whatever the complexity, this looked like a one-off procedure.
It is also not clear where a cell therapy approach might fit given that in CLL, for instance, the treatment landscape is changing fast. Owing to the early stage of the projects trials have focused on the sickest patients, but “the efficacy compels us to go earlier ... and response rates are such that the timeline for approval could be compressed”, said Dr Kalos.
“How that happens will, in our case, be up to Novartis.”