EBMT 2020 | Resisting immune rejection: engineered off-the-shelf T-cells

This is, again, a foray into the allogeneic off-the-shelf space, because obviously autologous products can be very useful in assessing the safety and efficacy and feasibility of targeting that particular antigen, but it’s not very scalable. And the field is moving right now to develop allogeneic cells that can be administered readily, and have very consistent and predictable potency. And another utilization of autologous products is that we are relying essentially on one or two cell doses, and therefore there’s a lot of effort to maximize their expansion and persistence. And this is often great to achieve durable remissions, but also oftentimes the cells have unwanted effects on normal tissue, such as B-cell aplasia and such. And so as we transition to the off-the-shelf, it would be, I think, very beneficial to develop a platform with predictable expansion and predictable contraction, and then so we can administer multiple doses.

And so these cell products will essentially resemble normal drug products with predictable pharmacokinetics and pharmacodynamics. And we know that it will undergo that many divisions and eventually crash, and then we can re-dose the patients to achieve the durable antitumor activity. But one thing to make that happen is that we need to make sure that these cells are not rejected by the host immune system. And patients have their own immune system, even though it is suppressed, but it’s still there. And if they start rejecting the cells, then it really will limit the benefit of all subsequent doses as they will be very short-lived. So we started developing approaches to prevent host rejection. We developed an engineered receptor that we call alloimmune defense receptor, or ADR, which targets activation markers on T and NK cells.

So basically, what we’re doing is we are redirecting the cytotoxicity of our therapeutic cell product, the CAR cell product, to also eliminate activated T cells and NK cells in the vicinity of that product. So they can just delete activated cells and protect themselves from rejection without touching resting populations that are circulating and nonactivated, therefore we presume a chunk of patient’s immune system and without having to deplete and to continuously ablate [inaudible] compartment. And so we’ve shown this, say in the recent publication, that it is quite effective in-vitro, and also in mouse models of allogeneic cell therapy of cancer, where we model rejection of C19 CAR-T cells in mice by human cells that are derived from a different donor. We show that the expression on this receptor need protects them from this allogeneic rejection, but both T and NK cells.

So we are very optimistic, and we’ll be testing this approach in the clinic, hopefully in the next a year or two. This will be, again, one of the bits that will comprize the next generation of cell therapies that can be administered off-the-shelf without the risk of graft-versus-host disease, because you can easily disarm those cells by knocking out TCR, going back to the previous question about the benefit of gene editing. But also you can arm them with this receptor so they will be protecting themselves against the attack of the immune system of the host. And then potentially the same approach can be utilized to suppress graft-versus-host disease after stem cell transplant, by also selectively eliminating activated T cells that produce pathology in the graft-versus-host disease setting. So it’s a promising direction. We’re developing this approach in multiple indications, multiple settings.