CAR-T Meeting 2025 | In vivo CAR T-cell therapy: benefits and challenges that must be addressed

The big difference is an off-the-shelf product, one medicinal product for all patients, versus a separate medicinal product for each patient which we have in the current setting. A key for that is of course to have vectors that are highly specific for the T-cells in the patients. So you don’t want to have the CAR delivered into non-T-cells or even tumor cells. That has to be avoided. Therefore, you need to have engineered vector particles that will make sure that the CAR is delivered selectively into the T lymphocytes of the patient. But there are lots of open questions whether this can work, of course. 

One issue is the conditioning. So the lymphodepletion we currently do with conventional CAR T-cells is something you cannot do for in vivo because then you would eliminate the T-cells which are however the target for the vector to deliver the CAR. Something that has to be avoided. So we’ll see if in the absence of conditioning, CAR T-cell generation in the patients can work. Then will there be sufficient numbers of CAR T-cells generated to really eliminate the tumor cells? 

And then if that all should go well, there will be safety issues coming up which can only be addressed after long-term follow-up probably. So one question is, will there be an immune response against the CAR T-cells because you have the vector particles delivered together with the CAR to the patients? Will there be insertional oncogenesis, which could be a theoretical concern when vectors integrate into the genome. And probably, as we know from the history of gene therapy, other issues may come up as well. But nevertheless, it’s of course that would be a huge difference, maybe a revolutionary making to the whole CAR T-cell field if in vivo works since then we have a much less expensive and less complex manufacturing.

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