Shortening the time to manufacture CAR T-cells

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Published: 10 Dec 2017
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Dr Partow Kebriaei - MD Anderson Center, Houston, USA

Dr Kebriaei specks with ecancer at the 2017 ASH annual meeting about how shortening the time to manufacture CAR T-cells with "sleeping beauty system" supports T-cell engraftment and anti-tumour effects in patients with refractory CD19 tumours.

 

At MD Anderson what we have undertaken is we are using a second generation CAR construct that signals through CD28 and CD3 zeta targeting CD19. What’s unique about our product is that it’s using a non-viral transduction system, it’s a DNA transposon transposase system called Sleeping Beauty. We have been really leading the efforts to take this into the clinic. In what we call our first generation CAR we established the safety and feasibility of this product and now we really are looking and modifying the trial to assess efficacy. We’ve tweaked it some to see if we can improve results. So what I’m presenting at ASH this year is what we call our second generation trial in which the construct has been revised or modified so that we’ve switched out our IgG Fc domain for CD8 and, most importantly, we’ve shortened the manufacturing time. We don’t expand the cells as long ex vivo with the hope that the cells have less exhaustion. We’ve changed the study design so that patients need to have active disease to receive the cells so that we can get a sense of efficacy. What we’re presenting at the meeting this year is the results of eight patients that have been treated to date on this dose escalation study. We’ve completed our second dose level so patients have been dosed at a maximum of 1x107 CAR T-cells per kilogram. What we’re seeing encouragingly is that for the first time we’re able to detect the CAR T-cells in the peripheral blood, so we can detect the T-cells by flow as well as by PCR. In the first generation trial we could only detect by PCR. We’re also seeing responses, albeit transient, and for the first time we’re seeing cytokine storms. So we’ve had a maximum of grade 2 cytokine release. In general, however, the T-cells are still really well tolerated and the majority of patients just had grade 1 CRS. So in terms of the safety profile of this construct it’s very safe, in terms of efficacy we still need to work on the efficacy. We’re still dose escalating so we’ll see what happens at the higher dose levels but it is encouraging that we’re able to now detect these cells in the peripheral blood by flow.

Ultimately our goal is to go towards what we call this point of care product because one of the limitations in all of these CAR constructs is that it takes time to manufacture the product. So until we use an off the shelf product you really need to have a product that you can use on demand. So our next generation trial will have an IL-15, a membrane bound IL-15, input into the construct so that hopefully really all of the culturing or the expansion can occur in vivo. The idea is we can take a patient, pherese the patient, they come in to the hospital and they get one or two days of lymphodepletion and then they get their CAR infused right back. That’s the ultimate goal and so we hope to open that trial in the spring.

Are you going to be looking to recruit more patients?

The current trial is a four dose level trial so we will max at 24 patients. In the next trial we’re going to be looking at two dose levels. It’s going to be a smaller feasibility trial initially at this point of care and we will see what happens.