Some stem-cell-based regenerative therapies will draw on cells from individual patients. Some won’t. How will those alternatives shake out?

Regenerative treatments based on induced pluripotent stem cells (iPSCs) fall into two camps, with the cells drawn either from each patient (autologous) or built off-the-shelf from donor cells (allogeneic). Writing for Nature about manufacturing iPSC-based medicines, I’m struck by the large bets being placed on allogeneic approaches, which haven’t yet been proven clinically.

There’s a lot of progress, in the lab, in solving the obvious big problem with these outside cells: reconfiguring them to slide under the radar of your immune system. Experiments aim to copy the molecular mechanisms by which tumors and fetal cells dodge immune bullets, or to remove the major histocompatibility complex (MHC) molecules by which your T cells recognize your own cells, and/or to pull off many other ingenious genetic tricks.

The potential benefits for off-the-shelf treatments are obvious, beginning with better control, availability and cost than painstakingly created individual treatments.

No surprise, cell therapies will not come cheap. Chimeric antigen receptor (CAR) T cell treatments for blood cancers (the remarkable predecessors for today’s cell therapy candidates) cost around a million bucks per patient. That’s too much for large numbers of cancer patients and waaay too much for the chronic conditions suffered by millions such as Parkinson’s disease, diabetes and heart disease.

And as tricky as it is to make autologous CAR-T cells, even years after those treatments have been commercialized, stem-cell-based therapies are even more laborious.

CAR-T cells are genetically modified to create a receptor protein that goes after bad B cells. OK, not easy. But stem-cell-based therapies require vastly greater modifications, in two huge steps. First, the cells must be pulled back to a pluripotent state. Second, these pluripotent cells must be differentiated into neurons or pancreatic islet cells or heart cells. This differentiation process recapitulates normal cell development and requires weeks or months. Each cell line behaves a little differently during this process. The safety and effectiveness of the results are not givens.

So, nice to need to perform all this magic only once!

Among studies of early allogeneic candidates, BlueRock Therapeutics has launched a trial of dopamine-producing cells that might help with Parkinson’s disease. (Curiously, the cells are derived from embryonic stem cells, not iPSCs; understandably, the company isn’t emphasizing that point.) The first of 10 patients received a transplant in June in surgery at Memorial Sloan Kettering.

Notably, the subjects in the BlueRock study will be given drugs to partly suppress the immune reaction.

This downside is one reason Ole Isacson of McLean Hospital, a pioneer in stem-cell-based treatments for Parkinson’s disease who published a key 2015 paper on research in primates, remains in the autologous camp.

“With allogeneic cells in general, there’s still recognition by the immune system, even in the brain, of these foreign cells,” Isacson noted during an Endpoints seminar last month.

Moreover, autologous cells integrate better within the primate brain and deliver better recoveries, said Isacson. He pointed to a March paper by University of Wisconsin researchers showing that autologous dopamine-producing cells functionally outperformed allogeneic cells in rhesus monkeys that model Parkinson’s.

Isacson also suggested that creating individualized stem cells and then redifferentiated therapeutic cells will be done efficiently and affordably in the foreseeable future with closed-loop automated systems such as those being developed by Cellino Biotech.

Talking with researchers in various forms of cell therapies during the past year, I found that many expect walk-before-you-run progress: When and if autologous treatments work, there will be redoubled work on allogeneic alternatives.

“The immune system is an amazing force of nature that can detect the tiniest little differences,” Jeffrey Bluestone of Sonoma Biotherapeutics told me in an interview for a Nature story on regulatory T cells. “Engineering an invisible cell without the immune system ever seeing it will be a challenge… Having said all that, though, I think the field is moving really well in that space.”

Image of iPSC-derived neurons by Matheus Victor of MIT’s Li-Huei Tsai lab.