So far, the excitement surrounding “living drugs” is that of pioneer work, with Carl June and Steve Rosenberg playing the roles of Lewis and Clark or the Wright brothers.
But if you turned on the high beams at the virtual annual meeting of the American Society of Gene and Cell Therapy (ASGCT) this week (and left aside the question of just who was going to pay for it, and just how), you could see a future where such living drugs might be all but ubiquitous – and, to top it off, far more complex than today’s T cells that contain a chimeric antigen receptor, or lack the CCR5 receptor.
In his George Stamatoyannopoulos Memorial Lecture, June, who had a key role in developing Kymriah (tisagenlecleucel, Novartis AG), described the first clinical trial of CAR T cells with three separate CRISPR edits, which he and colleagues reported in Science earlier in 2020. And at the Thursday plenary, the presentation of the highest-rated abstracts of the conference included work describing the “generation of islet-specific gene edited regulatory T cells for restoration of immune tolerance in type 1 diabetes” (T1D).
The history of cell transplantation for diabetes shows just how difficult it has been to realize the promise of cells as living drugs. Type 1 diabetes is an autoimmune disease, where T cells destroy insulin-producing pancreatic beta cells.
As autoimmune diseases go, it is not, in principle, a complicated one. The only cells that are attacked are pancreatic beta cells, and their restoration can restore insulin secretion to patients.
In practice, after decades of trying, beta cell transplantation is still an experimental procedure, and according to the most recently published data of the Collaborative Islet Transplant Registry, only about 25% of transplanted patients for whom follow-up data are available no longer need insulin injections, and many grafts stop working over time.
There have been multiple challenges, including procuring cells and keeping them viable. One key issue is that transplantation does not correct the underlying autoimmune disease that killed the beta cells in the first place.
Regulatory T cells, Peter Cook explained at the plenary session, block inflammatory immune responses through multiple mechanisms, which has led to interest in developing them for T1D.
But T cells can switch fates, and if immune dampening regulatory T cells converted to inflammatory effector T cells, there is a risk of transplants leaving patients worse off than before.
Cook, a senior scientist at the Seattle Children’s Research Institute, and his team developed T cells with two major edits.
First, the scientists added a promoter that strongly drives T cells toward a regulatory type, which restrains the actions of effector T cells.
The team then added a T-cell receptor to make their regulatory T cells islet-specific.
At the plenary, Cook described using gene-edited regulatory T cells to block both “matched” effector T cells containing the same T-cell receptor, and “bystander” T cells that also attacked islet cells, but whose T-cell receptor did not fully match that of the edited regulatory T cells.
Their effect against bystander cells, Cook said, shows that the edited cells “have the potential to broadly inhibit islet-specific T cells in the pancreas and are not limited to a single antigen.”
Finally, the team added a chemically induced signaling complex (CISC) that mimicked interleukin-2 signaling to give their cells a leg up against both effector T cells and naturally occurring regulatory T cells. In mice, an infusion of the cells “almost completely suppressed hypoglycemia” for up to 50 days after transplantation.
Cook said the cells could be transplanted as a combination therapy with islet cells, and could also be adapted to other autoimmune diseases by changing the T-cell receptor.