The Q&A – Opportunities and challenges with CAR-T in acute lymphoblastic leukaemia

Later this week, Novartis' tisagenlecleucel – more commonly known as CTL019 – could move a step closer to becoming the first approved CAR-T therapy. On Wednesday (July 12) an FDA advisory committee will review the cell-based product as a potential treatment for relapsed/refractory B-cell acute lymphoblastic leukaemia (ALL) in paediatric and adolescent patients.

Ahead of the AdCom review, we look at some of the key opportunities and challenges associated with CAR-T therapy for the treatment of ALL based on recent conversations with a panel of key opinion leaders who are heavily involved with this therapeutic modality.

Responses in ALL are dramatic…

Key opinion leaders (KOLs) describe the responses to anti-CD19 CAR-T therapies as exceptional and unprecedented in patients with ALL. CAR-T treatments, they add, are addressing unmet needs and will revolutionise treatment of this disease…

"Everybody is impressed. For multiply relapsed ALL, a 90 percent remission rate after a month of therapy is beyond anything that has ever been out there for relapsed patients with a new drug. The complete remission rates at the end of the first month are outstanding. With the original CTL019, where we have the information [for the longest period of time], we still have 50-60 percent of patients in remission in a year, so that’s pretty incredible."

…But relapses are a concern

Two main types of relapses to anti-CD19 CAR-T treatment have been identified. The first is CD19-positive relapse, where the leukaemia phenotype is the same as before treatment but the T cells become hypofunctional. The other form is CD19-negative relapse, where the disease recurs with the loss or downregulation of CD19 on the leukaemia cells (antigen loss or escape). Although high response rates have been achieved in patients with ALL, KOLs are alarmed by CD19-negative relapses in particular and view them as a real concern. Estimated to account for approximately a third of all relapses, CD19-negative relapses are of greater concern as retreatment with an alternative CAR-T cell therapy may not be beneficial or sustainable from both a clinical and cost perspective.

"The problem with ALL is, and is going to be, relapses. Between 20 to 50 percent of patients relapse, many with CD19-negative disease. Nevertheless, these are extremely heavily pre-treated refractory patients with no treatment options, and I still think that the outcomes are remarkable."

Will durability differentiate the anti-CD19 CAR-T products?

Persistence and durability of remissions will be a defining feature of first-generation anti-CD19 CAR-T therapies, argue KOLs, who speculate this may be dependent on each CAR-T product’s specific manufacturing processes. Longer follow-ups will be essential to tease out any subtle differences.

"I think the durability is really linked to the persistence of the CAR-T cell in vivo. The persistence is very likely to be different for the different CAR-T cell products. All different products and several manufacturing programmes have shown the high response rates. What I think will end up being different is the persistence rates and the durability of responses among different CAR-T cell products."

Serious side-effects but more manageable in paediatric and adolescent patients

Versus Novartis' application in paediatric and adolescent ALL patients, KOLs agree that more serious safety concerns related to anti-CD19 CAR-T therapy have been observed in adult patients with ALL, while side-effects – including cytokine release syndrome (CRS) – are viewed as more manageable and reversible in paediatric and younger patients. This difference in toxicity can possibly be attributed to the fact that adult patients with ALL generally have more comorbidities resulting from prior intensive chemotherapy treatments and are therefore less able to tolerate CAR-T therapies.

"I think the paediatric [patients] are going to handle this much better. A 5 or 10 year-old who has a much healthier body overall, is going to tolerate CAR-T much better than a 40, 50, or 60-year-old. In upfront therapies for ALL, now 40 -year-olds and under get treated with paediatric protocols. Over 40, it’s too much on the body, your liver is not going to work in the same way. When the body goes through this storm, paediatric patients are just so much healthier than adults."

Some KOLs also make a distinction between the mortality rates for CAR-T versus allogeneic hematopoietic stem cell transplantation (HSCT),  stating that the latter has higher mortality rates (10 to 40 percent) overall compared to rates for CAR-T cell treatment.

Companies must ensure efficient streamlining of manufacturing and distribution to meet patient demand

Scaling-up the manufacturing of autologous CAR-T cell therapies will be crucial to ensure broad patient access and sustainability. At present, manufacturing is centralised and conducted at a facility off-site. Simultaneously, KOLs strongly believe that the manufacturing and distribution processes must be streamlined to avoid any delays in the production supply chain.

One issue that does provoke significant concern in some KOLs are the current manufacturing turnaround times for autologous CAR-Ts. Two KOLs state that current turnaround times have been longer than two or three weeks. As patients with relapsed/refractory disease have a narrow timeframe to wait for treatment, KOLs point out that any manufacturing site delays could be detrimental. Furthermore, failure to treat certain patients due to disease progression (while awaiting CAR-T therapy due to manufacturing process) has also sparked debate as to whether response rates should be measured using the intend to treat cohort or only those patients who actually receive therapy. If the latter metric is used, does this qualify as patient enrichment?

"There’s some thinking ‘outside the box’ strategies for on-site manufacturing versus optimising that whole path to a centralised manufacturing centre. We do this all the time with bone marrow transplants. Somebody needs to get [cells] collected, then it needs to get shipped to a recipient at a different place. Allotransplant is individualised too.  There is a precedent for this type of process. There’s no manufacturing in stem cell transplant, it’s just a collection and delivery, but it’s a similar process."

CAR-T cells unlikely to replace HSCT but will complement their use

An existing competitive threat to CAR-T therapies is the availability of HSCT that can offer patients with relapsed/refractory haematological cancer a significant chance of a cure. Another valuable option may be to administer CAR-T cell treatment to bridge patients to HSCT, or reserve them as a salvage treatment for when transplantation fails. A number of KOLs refuse to rule out the future possibility of autologous CAR-T cells eventually replacing transplant in some patient groups; however, this will depend on outcomes of head-to-head studies. Across the haematological cancer landscape, however, the majority of KOLs believe that CAR-T treatments will most likely complement the use of transplantation.

"With paediatric and adult ALL, it’s a bridge to transplantation, but patients going into allogeneic stem cell transplantation appear to do better. When you’re entering into a transplant in remission, the results have been excellent, especially in paediatrics, and these have been refractory children. The ones that have gone onto transplantation are having about a 60 to 80 percent disease-free survival post-transplant. Those results are very, very early, but otherwise you would expect a high degree of relapse after allogeneic transplant. The results are very impressive."


For more details about our recently published report on the CAR-T development landscape click here

For recent Insight, Analysis & Views coverage of CAR-T-related industry news see…

Spotlight On: All eyes on a CAR-T AdCom, but the allogeneic approach attracts sideways glances

Spotlight On: And then there were two – Logistics of CAR-T delivery come into focus as Kite confirms FDA priority review for axicabtegene ciloleucel

ViewPoints: The data's all here for Kite and Novartis, but will there be a failure to launch?

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