CTA: Will the CRISPR babies situation scare people off from the gene-editing field as a whole?
Dr Levine: Well, I’ll tell you, that’s a huge concern, and I was on a panel at the World Affairs Council in Philadelphia with my colleague from Penn, Kiran [Kiran Musunuru, MD, PhD, MPH, associate professor of medicine in genetics and associate professor of Medicine, Penn Medicine], who has been quoted extensively in press reports. And [the ISCT is] concerned that when something like what happened in China is absorbed by the lay public that it conflates the legitimate pursuit of investigation of experimental therapies with this disaster.2
We have enough problems in the scientific community, with the public acceptance of climate change, genetically modified food, and vaccines. We don’t need this on top of it.
CTA: I heard a lot at about T-cell exhaustion at the 2018 American Society of Hematology (ASH) meeting, especially as it related to the manufacture of universal CAR-T. Can you speak to that?
Dr Levine: Well, that’s a big question for the allogeneic therapies, [will] the ability of those cells persist long enough to mediate the therapeutic effect only as [a] transition to a definitive therapy, or could it ever be a standalone therapy, like autologous CAR-T cells?
And to make a large number of doses, the protocols that I’ve seen have a culture period that is significantly longer than the autologous culture. So, something that will have to be answered is the combination of a longer culture, which we know generates a phenotype that does not engraft long; a limiting factor in [the] efficacy of allogeneic CAR cells.
Additionally, the rejection of the graft T cells by the recipient we know is an issue for [the] persistence of allogeneic cells.
I understand and support the thesis that the rationale for allogeneic T-cell therapies [is] that there are patients from whom one cannot obtain or generate sufficient autologous cells. Certainly, infants [and] patients that have been heavily pretreated.
But I don’t accept the rationale of cost/benefit, because almost every patient is likely to have to have an allogeneic T-cell therapy coupled with an allogeneic stem cell transplant. There may be a few in whom that is not needed, but the vast majority that have been reported at ASH and previously have required transition to an allogeneic stem cell transplant.
It’s not an apples-to-apples comparison of allogeneic CAR-T to autologous CAR-T. You’re comparing allogeneic CAR-T to blinatumomab or some other bridging therapy.
Another rationale for the allogeneic therapy is that they can be pre-positioned and available fairly quickly, where the autologous therapies have to be generated, and it would be 2 or 3 weeks, or whatever it is, for that patient to be treated.
Now, that’s another legitimate rationale, and that’s what the presenter for Amgen said [at ASH] when he was asked the question about comparing allo[geneic] versus auto[logous]. But what he didn’t say is [that there is a] need for continuous infusion of blinatumomab and probably [their] BiTE, as well. And in terms of convenience in administration, I’ll leave it to physicians — I’m not one, but I’ll leave it to physicians and patients to tell you about continuous administration.
[Patients are] catheterized, and they have to wear a bag or some kind of cartridge for the infusion to proceed.