Enabling allogeneic therapies: CIRM‐funded strategies for immune tolerance and immune evasion

A major goal for the field of regenerative medicine is to enable the safe and durable engraftment of allogeneic tissues and organs. In contrast to autologous therapies, allogeneic therapies can be produced for many patients, thus reducing costs and increasing availability. However, the need to overcome strong immune system barriers to engraftment poses a significant biological challenge to widespread adoption of allogeneic therapies. While the use of powerful immunosuppressant drugs has enabled the engraftment of lifesaving organ transplants, these drugs have serious side effects and often the organ is eventually rejected by the recipient immune system. Two conceptually different strategies have emerged to enable durable engraftment of allogeneic therapies in the absence of immune suppression. One strategy is to induce immune tolerance of the transplant, either by creating “mixed chimerism” in the hematopoietic system, or by retraining the immune system using modified thymic epithelial cells. The second strategy is to evade the immune system altogether, either by engineering the donor tissue to be “invisible” to the immune system, or by sequestering the donor tissue in an immune impermeable barrier. We give examples of research funded by the California Institute for Regenerative Medicine (CIRM) in each of these areas, ranging from early discovery-stage work through clinical trials. The advancements that are being made in this area hold promise that many more patients will be able to benefit from regenerative medicine therapies in the future. Significance statement For cell and tissue therapies to become widely accessible will ultimately require the success of off-the-shelf allogeneic products that can be administered to patients regardless of immune compatibility with the donor tissue. Since the long-term use of immunosuppressive drugs renders patients subject to infectious disease and other side effects, it is critical to develop alternative methods to overcome immune barriers to engraftment. The California Institute for Regenerative Medicine (CIRM) has funded multiple programs, in different disease areas and at different stages of therapeutic development, that are tackling this challenge. This article summarizes the main approaches that are being taken in this rapidly moving field and gives examples of specific programs that CIRM has funded in these different areas.

Abstract licence: CC BY-NC

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