CAR-T cell therapy for ALL: Current challenges and future approaches

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Published: 23 Jan 2020
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Dr Sara Ghorashian - University College London, London, UK

Dr Sara Ghorashian speaks to ecancer at the 2020 ALL Assembly meeting in Frankfurt about the current challenges in the field of CAR-T cell therapy.

She describes the CARPALL study, which uses a different type of CAR-T cell that signals at a lower affinity for CD-19 which has a more favourable toxicity profile in both the adult and paediatric settings.

Dr Ghorashian also discusses CAR-T cell persistence and how the therapeutic effects can disappear in a minority of patients.

She states that access to CAR-T cell therapy is limited due to its associated costs, but these can be mitigated if the therapy is administered in an ambulatory setting.

ecancer's filming has been kindly supported by Amgen through the ecancer Global Foundation. ecancer is editorially independent and there is no influence over content.
 

It was an interactive session that we designed with a view to looking at the major challenges that are faced by the field at the moment. I identified discussions relating to toxicity approaches, looking at CD19 negative relapse, looking at CAR T-cell persistence and whether it’s required and what strategies can be used to overcome a limited CAR T-cell persistence and what to do for the patient from whom an autologous product cannot be generated.

How are the toxicities being addressed?

Toxicity in particular is something that’s close to my heart because we generated a CAR T-cell that signals at a slightly lower affinity for CD19 and so that’s an approach that we’ve taken forward in the CARPALL studies and in the ALLCAR19 studies that were presented at ASH this year. This is a product that has now been taken forward for a licensing study, potentially, by Autolus and it’s now designated Auto-1. So I’m very excited to see how that bears out in the future but essentially the use of Auto-1, both in a paediatric and an adult setting, has shown that you can have a very favourable toxicity profile with no patients having severe cytokine release syndrome when treated with those two products.

Were there any interesting questions or discussions?

A lot of people were concerned about the need for CAR T-cell persistence, how long you have to have the CAR T-cell persistence and what you can do if you don’t get CAR T-cell persistence. That has been something which clearly is troubling people who deliver CAR T-cell therapy and then they notice that the CAR T-cells disappear quite quickly. It’s only seen in the minority of patients as far as we can tell in terms of real world use of CAR T-cell therapy but what to do next is a concern. So we discussed how it firstly is associated with a higher relapse rate in certain contexts and therefore if you have CAR T-cell persistence for less than six months it probably is worth considering whether you can go on to deliver an adjunctive treatment. At the moment probably adjunctive transplant is the therapy worth thinking about. I reviewed the abstract data from the Children’s Hospital of Pennsylvania in relation to the use of checkpoint blockade, we looked at the data from Seattle in delivery of T-cells that express CD19 to try and boost CAR T-cell persistence but those strategies are sometimes quite laborious and difficult and aren’t completely toxicity-free, of course.

How accessible is this treatment?

Access to the licensed CAR T-cell therapies is limited by their prohibitive cost and that’s just the cost for the product, there is also then the treatment which is most straightforwardly delivered potentially in an in-patient setting with an in-patient admission of up to five weeks. So ways to get around that are to deliver it in an ambulatory setting, for example, and that will at least mitigate some of the costs because you’re not having a patient sitting on a ward for that length of time. US centres have demonstrated that you can deliver it safely in that context so maybe that will increase some access to the licensed CAR T-cell products. But for other middle income and lower income countries I think it has to be on the basis of academic delivery, potentially, within studies that are run in the country themselves using the regulatory authorities in that country to deliver treatments on a study basis. Because clearly the cost of developing these as pharmaceuticals comes with a significant price tag.

What is your key message?
It’s important to understand that we’re not there yet with just Kymriah alone, for example in the setting of paediatric ALL which is the context that I work in. There’s a lot of work to be done in trying to optimise CAR T-cell therapy for the future and to overcome the challenges that I’ve already mentioned, in other words the toxicity that can exist if you treat a patient with a heavy bone marrow disease burden and trying to eliminate CD19 negative relapse in trying to provide an answer for patients for whom an autologous product can’t be generated. Looking at more clever approaches, really trying to unlock the potential for the best anti-tumour efficacy in a CAR T-cell product.