Cell Therapy's Biggest Problem is Biology, not Manufacturing

If you ask most people why cell therapy has not lived up to its potential they will almost unanimously point to one thing - manufacturing. While I certainly agree manufacturing is a problem (I am in the camp of point-of-care production is the future), I don’t think it is the biggest problem. Biology is cell therapies' biggest problem.

If we waved a magic wand and made today’s approved CARs, TILs and edited HSCs only cost $2k you would undoubtedly improve their profit margins and financial sustainability but I don’t believe you would dramatically change patient impact. Regardless of cost, today’s cell therapies would never be first-line treatments because of their biological handicaps.

Autologous CARs, while highly effective, have long-term safety risks that would be unacceptable for a first line therapy. Even if the risk of causing subsequent malignancies is proven to be equivalent to typical first line chemo, the prospect of being immune compromised for life would be a dealbreaker (if your CAR-Ts are persisting they are also continuing to kill your B cells).

Currently approved TILs don’t have any genetic modification risks but the high dose IL-2 requirements bring patients to the edge of death. That level of toxicity would be unacceptable in a first-line setting.

The recently approved CRISPR edited HSCs are a substantial scientific milestone, yet they have been a commercial flop. Not because of their cost, but because the conditioning regimen required is extremely toxic and only justifiable for the most severe cases of sickle cell and beta thalassemia that are resistant to current treatments.

To accomplish the titanic shift in medicine that cell therapies have the potential for, we need to evolve our thinking. Cells are an attractive therapeutic modality because they are capable of complex interactions. The intricacies of today's most challenging diseases across oncology, autoimmunity, neurodegeneration, etc necessitate equally nuanced cellular strategies to make that big impact. Current cell therapies use simple, brute force strategies to ‘program’ a cell. Smashing our way through the genome with editing and insertion tools ignores the fact that our cells are generally designed for ‘software’ changes not ‘hardware’ changes. After all the DNA in the vast majority of our cells is identical, what sets apart a skin cell from a neuron is not its genetic sequence but rather what transcriptional ‘programs’ are on. Only genetic diseases are likely to necessitate a hardware change because the DNA is the problem, for almost everything else we shouldn’t have to resort to that.

In a world where we think of cell software, we can imagine modifying multiple aspects of a cell simultaneously to drive the desired outcome (think of it as giving a cell a program with multiple lines of code whereas current approaches generally try to hardwire in one or two changes). If we adopt a software approach, one could make cell therapies much safer, more powerful AND more sophisticated. Lets go back to those approved therapies:

CAR-T: A transient (e.g. RNA-based) CAR would eliminate the long-term safety risk. If persistence is a concern, one could repeat dose. Now perhaps CARs can be first line (if coupled with cost-efficient, point of care, manufacturing) and they’d probably beat out bispecifics and ADCs.

TILs: The IL-2 administration is necessary because the TILs generated ex vivo are often exhausted T cells with little functional capacity. Delivery of a few transient rejuvenating factors could substantially improve performance while eliminating the harsh toxicities - a TIL could now be an attractive therapy for the adjuvant setting.

Edited HSCs: These are often addressing genetic diseases that DO necessitate tampering with the DNA. However, they require conditioning because the resultant HSCs tend to struggle to engraft. Transient components that drive survival and bone marrow homing pathways could potentially eliminate any toxic conditioning risk

Cell therapies are clearly in the ‘trough of disillusionment’ at the moment - many promises were made and broken. We need to learn the right lessons from these experiences and build a future class of cell therapies that can have massive patient impact while remaining commercially compelling. Cell therapies can and should be the first treatment patients receive across a whole range of ailments. To get there, we need to stay away from the genome (i.e. transient cargos only), and stay close to the patients (point of care production).