NCI CARs for childhood ALL and neuroblastoma: the promise and potential pitfalls

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Published: 23 Sep 2016
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Dr Daniel Lee - University of Virginia, Charlottesville, USA

Dr Lee meets with ecancertv at Childhood Cancer 2016 to discuss results from clinical trials of immunotherapies for neuroblastoma and acute lymphoblastic leukaemia.

He describes CD19 T cells successfully treating leukaemia within the cerebrospinal fluid, and the ongoing recruitment of patients for GD2 CAR T cell treatment for osteosarcoma and neuroblastoma.

In both trials, Dr Lee describes low toxicity and neurotoxicity for patients, and introduces a CD22 CAR T cell trial still enrolling patients.


Childhood Cancer 2016

NCI CARs for childhood ALL and neuroblastoma: the promise and potential pitfalls

Dr Daniel Lee - University of Virginia, Charlottesville, USA

I presented two clinical trials - our CD19 chimeric antigen receptor clinical trial in paediatric ALL and B-cell lymphomas as well as a GD2 CAR T-cell trial for primarily osteosarcoma with a few neuroblastoma patients.

Our first trial, the CD19 CAR T-cell trial, was quite pivotal, as have been several of the other trials at the other institutions in the US. At the present time we have data on 46 patients, children and young adults, with refractory relapsed leukaemia mostly. We gave them a single dose of the CD19 CAR T-cells after most often a light chemotherapy prep regimen and we had 60-65% complete response rate that was an intent to treat analysis. The intent to treat analysis allows us to account for every single patient that we have enrolled and every single patient that we did enrol had detectable disease at the time we treated them. So I think that that’s really across the board, when you look at multiple institutions people report different response rates but in reality I think they’re all about the same. Importantly in our study one of the key findings was that we could quite reliably and effectively treat leukaemia that had gone to the spinal fluid or even the brain. We had five patients with such disease, two were quite extensive disease in the brain and in the spinal fluid, and we were able to safely and effectively eradicate CNS leukaemia as well as systemic leukaemia with a single intravenous infusion of the CAR T-cells. The CAR cells migrate to the brain and spinal fluid and kill off tumour there.

So really that’s quite important because there has not been another effective therapy to treat CNS leukaemia in the past thirty or so years and we still are using multiple doses of intrathecal chemotherapy with or without high doses of radiation, all of which have bad or chronic side effects. So this is a completely new modality of treating CNS leukaemia so it’s quite exciting and without, apparently, any lasting toxicities at this point.

Could you tell us a little more about the second trial you mentioned?

I recently moved from the paediatric oncology branch at the NCI where these trials were conducted. The GD2 CAR T-cell trial at the NCI treated twelve patients with osteosarcoma, which is GD2 positive, and two patients with neuroblastoma which obviously is also GD2 positive. We’re still enrolling patients so the final data analysis is not out. We had to start at very low doses of cells because we were quite concerned, given the experience with the GD2 antibodies in neuroblastoma, of neurotoxicity. We were quite concerned that we would generate a severe neurotoxicity in these patients. So we started with very low doses and we’ve incorporated a suicide vector in the CAR itself which allows us to give an inert drug that would kill off all of the CAR T-cells if we ran into extensive problems. That hasn’t happened yet and we haven’t had to test it. At the most recent higher dose levels we’re starting to see some expansion of the CAR T-cells and some cytokine release syndrome which has been the hallmark of efficacy in the CD19 CAR experience. So extrapolating from that we think this is active but importantly we have not seen any neurotoxicity whatsoever in these patients.

Where next for your research?

The CD19 CAR T-cell trial we had at the NCI was independent of pharma and with my departure we closed that protocol. We actually still have a CD22 CAR T-cell trial which is a first in human trial being done in paediatrics which is a rarity these days that a first in human trial is being done in paediatrics in anything. But that’s still open and enrolling at the NCI under the guise of Dr Terry Fry. The GD2 CAR trial we’re still enrolling and we’ll see how active it is as we get to these higher dose levels and how promising that looks. For other reasons it might be advantageous to incorporate different motifs in the GD2 CAR because in general it’s harder to treat solid tumours than the leukaemias and lymphomas and you really need an extra push for the cells in order to get effective therapies, I think. It’s just unclear as to what that extra thing might be, it’s an active area of ongoing investigation.