A Map and a Primitive Blueprint for Moving Ahead With Clinical Xenotransplantation

The solution to the shortage of donor organs, the most significant limitation of transplantation, has evaded transplant clinicians since the early 1980s, when the development of calcineurin inhibitor–based immunosuppression made it feasible to achieve long-term success in most patients receiving a transplant for single end-stage organ failure.1 Improvements in gene editing and the development of new immunosuppressive drugs have improved the results in preclinical xenotransplantation to the point where cardiac and renal xenotransplantation has been tested in a preliminary manner under the cover of emergency Investigational New Drug Application applications approved by the Food and Drug Administration.2,3 Thus far, a single patient with a kidney transplant has survived >3 mo, whereas the other recipients have succumbed largely to early antibody-mediated rejection (AMR) in ≤60 d. In this issue of Transplantation, a suite of 4 articles from senior members of the International Xenotransplantation Association (IXA) is included that provide a map of where human xenotransplantation has been, followed by a blueprint for moving forward toward broad clinical implementation.3–7 These articles address (1) all previous human xenograft activity, (2) the history of xenotransplantation and the formation of professional and regulatory frameworks for development of xenotransplantation, (3) a generalized guide for the infectious evaluation of donor pigs and patient infectious considerations, and (4) a comprehensive summary of preclinical renal xenotransplantation that considers the appropriate donor pig, immunosuppressive protocols, and patient selection. These articles were written by members of IXA, many of whom toiled in obscurity for years, to bring xenotransplantation to the brink of clinical readiness. These articles serve as important reading and guides for anyone wishing to participate in early attempts at clinical implementation of xenotransplantation. Consideration of the roadmap provided in these manuscripts is critical for xenotransplantation to follow a more streamlined developmental pathway than allotransplantation. In a similar stage of development in 1963, renal allotransplantation had been performed in >300 patients worldwide, with <10% of patients surviving 90 d.8 In cardiac allotransplantation in 1969 with 100 transplants, only 24 patients lived 3 mo, 2 lived 6 mo, and 1 recipient lived 11 mo posttransplant.9 These poor results, combined with the inability of most transplant programs to directly participate in the development of key elements of allograft failure, especially the development of new immunosuppressive drugs, delayed widespread application of allotransplantation for >5 y. The articles provided in this issue are a key first step for anyone considering a serious run at clinical xenotransplantation. Understanding where the field has done intense investigation and what results were obtained can prevent the repetition of the same mistakes among multiple groups. The next step after evaluating these roadmaps for the development of xenotransplantation is for teams participating in early clinical xenotransplantation to develop robust investigative programs to evaluate problems encountered in clinical xenotransplantation. Unlike the 1960s, today it is more straightforward for transplant laboratories to be involved in all aspects of development in this field. Although evaluation in the study by Meier et al of the source donor pig makes recommendations for a relatively specific pig, this subject is far from settled and will require teams that can evaluate donor pigs free from the restraints placed by using pigs from a restrictive commercial source.5 AMR has been a significant component of early graft failure in nearly all human xenograft experiences, and as such, there is still work to be done as far as creating donor pigs with fewer xenoantigens.10 Improving the cross-matching is also critical and has been shown to reduce early graft loss in preclinical transplantation.11 Recent evaluation using very strict criteria suggest that at least 50% of all patients have anti-swine leukocyte antigen antibodies, and it will be very important for clinical teams to be able to identify which patients are devoid of these antibodies so that we can choose the patients most likely to benefit from xenotransplantation in our initial clinical trials.12 The study by Meier et al5 also addresses immunosuppressive protocols used in preclinical and clinical xenotransplantation and points out critical issues such as the improved efficacy of the costimulatory blockade of the CD40/CD154 pathway compared with the CD28/CD80–86 pathway. If current efforts at CD28/80–86 blockade continue to be plagued by glomerular AMR before 6 mo, it should be considered that previous data suggest that this approach has not worked as well as CD40/CD154 blockade.13 Fishman et al4 provided a straightforward blueprint for the necessary consideration to produce designated pathogen-free pigs, and for the surveillance of recipients for the development of zoonotic infections. The document by Fishman et al is minimal reading for any group considering participating in clinical xenotransplantation. Early clinical efforts were complicated by inadequate initial donor pig infectious issues, and this contributed to confusion in managing the initial cardiac recipient.2 Adherence to the pig management guidelines and patient surveillance in this article will simplify the performance of clinical trials and maximize opportunities for early patient success. The suite of articles compiled by senior IXA members in this issue of Transplantation highlights the decades of work that have placed xenotransplantation at the precipice of clinical application. Moving forward with careful consideration of this large body of work and strict adherence to critical and not unduly optimistic of the initial clinical results obtained can give xenotransplantation an abbreviated development based on learning from mistakes made during the development of clinical allotransplantation.