Blood cancers

CAR-T cell therapy still on the drawing board over composition & timing

Maximising the curative potential of chimeric antigen receptor (CAR) T cells will require a multi-pronged approach – improving CAR and cell product design, multivalent targeting and optimal timing of use.

Speaking to the limbic at Blood 2018, Professor Stan Riddell said the adoption of uniform ratios of CD4+ and CD8+ T cells in the cell product was one step forward.

“Using defined composition products is not a widely used strategy and I think it is an area that we can still innovate around and potentially really improve outcomes.”

“Unlike a drug where you know exactly what the dose is that you are going to give and what the pharmacokinetics are going to be, cells are very different. They are a living therapy. So if you are giving a different composition to every patient, it’s very hard to learn about the biology.”

“There are much more refined ways of selecting cells that have properties that could be very beneficial for immunotherapy and I think that what we will probably see as the years go by is more attention paid to that.”

Professor Riddell, from the University of Washington and director of the Immunotherapy Integrated Research Center at the Fred Hutchinson Cancer Research Center, said there was potential also to use the treatment earlier.

“Using a very effective therapy after patients have failed everything else is probably not the best way to use it. We need to figure out how to move it earlier in the course of treatment.”

He said despite the challenges, there was the potential for great benefit in adults and children.

“For example, children get multiple cycles – years of chemotherapy – that if they are very young has effects on growth and development that are lifelong. And so there is morbidity from doing that. CAR-T cells could reduce the amount of chemotherapy they would need to gain the same benefit.”

“The issue is it is challenging to figure out how to design those studies to really test that and do it in a way that optimises the safety for the patients. That’s our job as physicians; we need to figure out how to do that. We cure 90% of kids with chemotherapy alone and that is wonderful, but the issue is there is a cost to that. We have to see how we can balance that cost and potentially, incrementally maybe, move CAR-T cells earlier.”

He said clinicians were familiar with using combinations of chemotherapeutic drugs to optimise therapy.

“I think the same principle applies to immunotherapy. We have to identify what are the targets and then we have to figure out how to design the therapy to best capitalise on that. Is it a single multi-valent receptor? Is it different cell products which of course then increases the costs?”

He said antigen escape leading to relapse after CAR-T cells may be less of a problem when the therapy was used earlier.

“It may be less common if we use CAR-T cells earlier in the course because there is going to be less clonal heterogeneity. Remember these patients have been exposed to all kinds of chemotherapy which cause additional mutations, so again there may be an advantage of using it earlier.”

“I have treated cancer long enough to know that targeting one thing is often not going to be sufficient. We know that with chemo. We use combinations of chemotherapy precisely for that reason – because you will get cells that might be resistant to one drug of the four or five drugs you are using but they are not going to be resistant to all of them.”

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