Reviewing the State of Gene Editing to Make Cells Compatible Between Donor and Recipient
A sizable level of funding in academia and industry is devoted to the goal of enabling cell transplants between different individuals, with large and well funded pharma companies such as Astellas, Sana, and others involved. This would allow for the creation of cost-effective cell therapies of all sorts, in which the donor cells used in every patient originate from the same few well-vetted and well-controlled cell lines.
Logistics is everything in the realm of cell therapies, and the reason why autologous cell therapies, such as CAR-T treatments for cancer, are so expensive is that every treatment site must have the ability to extract cells from the patient, engineer them, slowly expand their numbers over weeks in carefully monitored culture conditions, and then perform quality control before use. Compare this with a universal cell line that is manufactured in one central location, with cells frozen down in a standardized way for storage, transport, and then use by any clinic capable of performing an infusion. It is a very different picture of cost and difficulty.
Regenerative medicine has come a long way since the derivation of the first human pluripotent stem cells (hPSC). As a community, we have become better at sourcing stem cells, differentiating them into therapeutic cell types and transplanting them to cure different diseases. To unlock the full potential of stem cell therapies, we need to overcome the immune barrier to transplantation. The human immune system is incredibly discerning in distinguishing between self and non-self, which could be viral or bacterial proteins, malignant cells, and, of course, cells from a genetically non-identical donor. Genetic differences between the donor and the recipient are recognized as alloantigens if they have never been encountered by the host's immune system before (as opposed to autoantigens) and may prompt allograft rejection.
Based on the nature of the genetic polymorphism and how/when they present themselves to the immune system, three types of alloantigens can be distinguished that, together, define the immune barrier. Human leukocyte antigens (HLA) are the immunodominant barrier to cell and tissue transplantation. Minor histocompatibility antigens (miHA) can vary in their expression from cell type to cell type. Neoantigens (NA) can accumulate during prolonged culture and pose a risk of rejection even of cells of autologous origin.
Initial attempts have focused primarily on the major histocompatibility barrier that is formed by the human leukocyte antigens (HLA). More recently, immune checkpoint inhibitors, such as PD-L1, CD47, or HLA-G, are being explored both, in the presence or absence of HLA, to mitigate immune rejection by the various cellular components of the immune system. In this review, we discuss progress in surmounting immune barriers to cell transplantation, with a particular focus on genetic engineering of human pluripotent stem cells and progenitor cells and the therapeutic cell types derived from them.
CAR T cells should soon be able to be produced at much lower cost, with T cells being extracted from the blood then readministered on the same day with the previously time consuming steps of activation, reprogramming, and expansion taking place in the patients body:
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