Bruce Levine, PhD, recalls a time in the early 2000s, when he and his colleagues from the University of Pennsylvania (UPenn) Perelman School of Medicine in Philadelphia were doing preclinical work on T cells and chimeric antigen receptor (CAR) T-cell (CAR-T) therapies and no one was paying any attention. The sessions on CAR-T cells at medical meetings would be on the last day of the conference, during odd hours within the conference program, or conducted “in a room nobody could find, [with] hardly anyone there,” he told Cancer Therapy Advisor. “Now there are overflow rooms, and overflow to the overflow, and it’s really incredible how this has exploded.”

Despite the exciting advancements that have been seen with immunomodulatory therapies since the early 2000s, there have been some developments that caused fresh concern about the use of such adoptive cell therapies. In a case report, a single blast cell that was collected in the apheresis product and not removed during manufacturing was reinfused to the patient.1 The leukemic cell had become transduced with the gene encoding the CD19 CAR, which bound in cis to the CD19 on the cell surface, masking it from recognition by CAR 19 T cells.

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The single leukemic B cell expressing the CAR targeting CD19 was delivered, this invisible cell expanded, and the patient under investigation died from progressive leukemia.

Cancer Therapy Advisor spoke to Dr Levine about how this could have happened, and broadly, what design approaches for CAR-based medications will help keep remissions durable and responses persistent. We asked Dr Levine, who is also president-elect of the International Society for Cell and Gene Therapy (ISCT), about the multipronged targeting approach that may be required when patients develop therapeutic resistance to CAR-T after their cells have lost the target antigen receptors that are necessary for recognition by the immune system.

[This interview has been edited and condensed for clarity.]

Cancer Therapy Advisor (CTA):  My first question is in relation to the finding that there was a single leukemic cell that snuck into the manufacturing process for one of the cell therapies made at the University of Pennsylvania. Can you discuss this? What are the differences between UPenn’s setup for manufacturing versus a commercial setting?

Dr Levine:  It still is true that there is no way to guarantee that there hasn’t been a leukemic cell coming through. We have made modifications to our manufacturing process for some trials that are being rolled out and to other trials that reduce the likelihood of that type of event happening by about a factor of a million. So, it is theoretically possible, because these patients do have leukemic cells circulating in their blood, and they are collected, and we do attempt to remove them and to enrich for T cells.  So, one can’t ever say never, I think — that it would never happen [again] — but certainly much less likely than it was.

To answer your question on manufacturing and our manufacturing facility, we actually have 2 facilities across the street from one another, and we have those equipped and operated in a way such that the final cell products are tested for safety, purity, and identity in accordance with criteria that we have submitted to the FDA [US Food and Drug Administration], and the FDA has accepted, or in some cases, [for which FDA] has requested modifications (that we have made).

The commercial operations have to adhere to the same things in the context of their clinical trials. What may differ slightly is in some of the testing methods or some of the equipment — and in the case of commercial approval, there may be some specifications that are different than [those used] during the clinical trials.