2020 article

Clinical xenotransplantation of the heart: At the watershed

Platt, J. L., Piedrahita, J. A., & Cascalho, M. (2020, August). JOURNAL OF HEART AND LUNG TRANSPLANTATION, Vol. 39, pp. 758–760.

By: J. Platt*, J. Piedrahita n & M. Cascalho*

co-author countries: France 🇫🇷 United States of America 🇺🇸
MeSH headings : Animals; Heart; Heart Transplantation; Primates; Swine; Transplantation, Heterologous
Source: Web Of Science
Added: August 10, 2020

See Related Article, page 751 See Related Article, page 751 Transplantation has been the preferred treatment for severe failure of the heart and other organs for more than 3 decades. But, for these decades and longer transplantation could be offered to few who could benefit because donated human organs were scarce. The most obvious solution to the scarcity of human hearts and other organs today, 30 years ago and decades before has been to use animals instead of humans as the source of organs, that is xenotransplantation. Yet, if xenotransplantation has been the most obvious solution, it also has seemed the most frustrating, a proverbial carrot on a stick, held just beyond reach by 3 barriers—immunity, physiologic incompatibility, and infection—of which immunity appeared most daunting.1Cascalho M Platt JL The immunological barrier to xenotransplantation.Immunity. 2001; 14: 437-446Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar The past 3 decades brought some dramatic advances in concept and technologies that might address the barriers to xenotransplantation. Yet, these advances were countered at every turn by discovery of new antigens, more incompatibilities and longer lists of zoonotic organisms. But in the current issue of Journal of Heart and Lung Transplantation, and in a previous report in another journal,2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar,3Längin M Mayr T Reichart B et al.Consistent success in life-supporting porcine cardiac xenotransplantation.Nature. 2018; 564: 430-433Crossref PubMed Scopus (142) Google Scholar Reichart et al2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar report > 3-month survival and function of orthotopic pig cardiac xenografts in baboons given clinically acceptable immunosuppression. The results “fulfill for the first time the preclinical efficacy” standard an International Society for Heart and Lung Transplantation (ISHLT) committee proposed as a premise for launching clinical trials in cardiac xenotransplantation.2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar,4Cooper DK Keogh AM Brink J et al.Report of the Xenotransplantation Advisory Committee of the International Society for Heart and Lung Transplantation: the present status of xenotransplantation and its potential role in the treatment of end-stage cardiac and pulmonary diseases.J Heart Lung Transplant. 2000; 19: 1125-1165Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar Did Reichart et al2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar finally capture the carrot and take, what they call “the final step toward clinical xenotransplantation” or did they just advance the stick, with unenumerated barriers keeping clinical application beyond reach? In 2000, an advisory committee of the ISHLT reported on the status of research into the barriers to clinical cardiac and pulmonary xenotransplantation and recommended that “a clinical trial should be considered when approximately 60% survival of life-supporting pig organs in non-human primates for a minimum of 3 months [has been achieved in] at least 10 animals.”4Cooper DK Keogh AM Brink J et al.Report of the Xenotransplantation Advisory Committee of the International Society for Heart and Lung Transplantation: the present status of xenotransplantation and its potential role in the treatment of end-stage cardiac and pulmonary diseases.J Heart Lung Transplant. 2000; 19: 1125-1165Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar The report culminated a decade of high profile discovery and debate. Key immune, physiologic, and infectious barriers to xenotransplantation had been identified and dramatic advances had been reported in genetic engineering, reproductive cloning, and development of biologic technologies for suppressing immunity and inducing tolerance (see Cascalho and Platt1Cascalho M Platt JL The immunological barrier to xenotransplantation.Immunity. 2001; 14: 437-446Abstract Full Text Full Text PDF PubMed Scopus (154) Google Scholar for review). But, the exciting advances that made clinical application seem so close also fueled concern about a long-known but little-understood endogenous retrovirus of pigs (porcine endogenous retrovirus) and about novel organisms that might develop in and spread beyond the immunosuppressed recipient. Although the need for organs for transplantation was urgent and increasing the ISHLT committee suggested only "consideration" of clinical trials because the proposed standard was still far from being achieved. Only 1 of numerous heterotopic cardiac xenografts in non-human primates had survived 3 months, and this graft suffered severe immune and inflammatory injury. Thus, the ISHLT committee correctly asserted that as of 2000, the “immune barriers [had] not yet been overcome.”4Cooper DK Keogh AM Brink J et al.Report of the Xenotransplantation Advisory Committee of the International Society for Heart and Lung Transplantation: the present status of xenotransplantation and its potential role in the treatment of end-stage cardiac and pulmonary diseases.J Heart Lung Transplant. 2000; 19: 1125-1165Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar Equally important was that only 1 orthotopic porcine cardiac xenograft had as yet supported the life of a non-human primate treated with clinically acceptable immunosuppression regimen and that for 39 days.5Vial CM Ostlie DJ Bhatti FN et al.Life supporting function for over one month of a transgenic porcine heart in a baboon.J Heart Lung Transplant. 2000; 19: 224-229Abstract Full Text Full Text PDF PubMed Scopus (97) Google Scholar In 2016, the prospects for clinical application of xenotransplantation changed dramatically. Mohiuddin et al6Mohiuddin MM Singh AK Corcoran PC et al.Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft.Nat Commun. 2016; 7: 11138Crossref PubMed Scopus (190) Google Scholar reported that heterotopic porcine cardiac xenografts expressing a human complement regulator (CD46) and human thrombomodulin and lacking Galα1-3Gal (owing targeting of α1,3-galactosyltransferase) could survive more than a year (up to 945 days) in baboons treated with a clinically-acceptable regimen that included anti-rhesus monkey CD40. Because the xenografts were heterotopic, the potential for providing physiologic support remained uncertain but this success in overcoming immune barriers reinvigorated discussion about whether and how xenotransplantation might be applied in patients. In 2018, Längin et al3Längin M Mayr T Reichart B et al.Consistent success in life-supporting porcine cardiac xenotransplantation.Nature. 2018; 564: 430-433Crossref PubMed Scopus (142) Google Scholar reported 4 successful orthotopic porcine xenografts in baboons that functioned until the recipients were euthanized, per protocol on days 90, 90, 182, and 195. The xenografts were from pigs with the same or similar genetic modifications as those used by Mohiuddin et al,6Mohiuddin MM Singh AK Corcoran PC et al.Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft.Nat Commun. 2016; 7: 11138Crossref PubMed Scopus (190) Google Scholar and the baboons were treated with immunosuppression similar to that of Mohiuddin et al6Mohiuddin MM Singh AK Corcoran PC et al.Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft.Nat Commun. 2016; 7: 11138Crossref PubMed Scopus (190) Google Scholar (plus an mammalian target of rapamycin inhibitor to limit myocardial remodeling7Kushwaha SS Raichlin E Sheinin Y et al.Sirolimus affects cardiomyocytes to reduce left ventricular mass in heart transplant recipients.Eur Heart J. 2008; 29: 2742-2750Crossref PubMed Scopus (41) Google Scholar). The present report2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar adds 4 orthotopic xenografts to the series. The xenografts in 2 recipients exhibited no evidence of significant rejection but systemic complications in the baboons with grafts harboring Cytomegalovirus (porcine cytomegalovirus [pCMV]) necessitated termination on Days 15 and 27. Two other xenografts functioned at 90 days, when the recipients were euthanized per protocol. Reichart et al2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar portray the 6 of 8 orthotopic xenografts functioning 3 months or longer as “well exceeding the key requirement of the ISHLT of the ISHLT International Advisory Board.” Some might questionwhether 6 of 8 xenografts functioning 3 months or more well exceeds or meets the ISHLT standard (60% of at least 10 life-supporting xenografts functioning 3 months4Cooper DK Keogh AM Brink J et al.Report of the Xenotransplantation Advisory Committee of the International Society for Heart and Lung Transplantation: the present status of xenotransplantation and its potential role in the treatment of end-stage cardiac and pulmonary diseases.J Heart Lung Transplant. 2000; 19: 1125-1165Abstract Full Text Full Text PDF PubMed Scopus (136) Google Scholar). We think giving more than passing mention to this standard formulated more than 15 years before the immunologic barriers had been overcome, obscures the significance of Reichart et al2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar’s accomplishment. If a porcine cardiac xenograft can support a non-human primate treated with a clinically acceptable regimen of immunosuppression; then, we must urgently consider what more, if anything, is needed to offer a cardiac xenograft to a dying human patient. And, we must explain why those facing imminent death for want of a transplant cannot be permitted xenotransplantation instead. Yet, after repeatedly claiming to have met or exceeded the standard for clinical application of xenotransplantation,2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar,3Längin M Mayr T Reichart B et al.Consistent success in life-supporting porcine cardiac xenotransplantation.Nature. 2018; 564: 430-433Crossref PubMed Scopus (142) Google Scholar Reichart et al2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar now demurs, saying only that “more experiments will be necessary.” But, the justification for more experiments is unpersuasive. The authors assert more experiments would “address the efficacy of humanized anti-CD40/CD40L,” but orthotopic cardiac xenografts are extraordinarily inefficient, complex, and insensitive system for testing the efficacy of immune modifiers; indeed, the efficacy of anti-CD40/CD40L was established using heterotopic xenografts.6Mohiuddin MM Singh AK Corcoran PC et al.Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft.Nat Commun. 2016; 7: 11138Crossref PubMed Scopus (190) Google Scholar Eight orthotopic xenografts are certainly too few to firmly establish the frequency of success and durability of function porcine cardiac xenografts in baboons. But, larger numbers of xenografts in baboons will reveal little more about the efficacy and durability xenografts might have in humans. The ISHLT committee wisely avoided stipulating a standard error for 60% survival or an end-point beyond 90 days because experimental transplants in non-human primates do not model and potentially misrepresent some key variables in clinical cardiac transplantation.8Platt JL Cascalho M Piedrahita JA Xenotransplantation: progress along paths uncertain from models to application.ILAR J. 2018; 59: 286-308Crossref PubMed Scopus (5) Google Scholar That is not to say experimentation in this model or in others should cease. Clinical cardiac xenotransplantation is likely to raise questions and challenges not foreseen today, and an experimental model could prove invaluable for addressing these. There is another perhaps more pressing reason to question what more experiments can accomplish. We suspect porcine cardiac xenografts in non-human primates might overestimate or misrepresent the barriers to clinical xenotransplantation.8Platt JL Cascalho M Piedrahita JA Xenotransplantation: progress along paths uncertain from models to application.ILAR J. 2018; 59: 286-308Crossref PubMed Scopus (5) Google Scholar The xenografts reported by Mohiuddin et al6Mohiuddin MM Singh AK Corcoran PC et al.Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft.Nat Commun. 2016; 7: 11138Crossref PubMed Scopus (190) Google Scholar and Reichart et al2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar were from pigs engineered to express human CD46 and human thrombomodulin to better regulate complement and coagulation in recipients. Yet, these and other proteins interact inefficiently with cognatepartners in baboons.9Lawson JH Platt JL Molecular barriers to xenotransplantation.Transplantation. 1996; 62: 303-310Crossref PubMed Scopus (162) Google Scholar Still more important is the possibility that the human proteins might elicit cellular and/or humoral immunity in baboons. Such immunity developing over time, perhaps when immunosuppression decreases to maintenance, might block regulatory functions or initiate injury to the grafts. Perhaps the anti-CD40 antibodies Mohiuddin et al6Mohiuddin MM Singh AK Corcoran PC et al.Chimeric 2C10R4 anti-CD40 antibody therapy is critical for long-term survival of GTKO.hCD46.hTBM pig-to-primate cardiac xenograft.Nat Commun. 2016; 7: 11138Crossref PubMed Scopus (190) Google Scholar considers essential are needed to disrupt immunity to the human proteins. Since intensity of immunosuppression could limit clinical application of xenotransplantation, it would be ironic if humans were found to need less intense regimens than baboons because humans are tolerant to the products of these transgenes. Of course, clinical trials might reveal higher or different barriers to xenotransplantation in humans than in baboons. But, that possibility has eluded detection in Reichart et al2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar’s model, and it would seem unlikely that more experiments would overcome the deficiency. Nor will the conduct of more porcine xenografts in baboons reveal much about the barrier posed by infection. The microorganisms of pigs known to be capable of infecting humans have been identified almost entirely by investigation of humans and pigs. Indeed, concerns about porcine endogenous retrovirus arose from investigation of human and pig cells in culture and the waning of those concerns from investigation of human contact with pig organs and xenografts.10Paradis K Langford G Long Z et al.Search for cross-species transmission of porcine endogenous retrovirus in patients treated with living pig tissue. The XEN 111 Study Group.Science. 1999; 285: 1236-1241Crossref PubMed Scopus (631) Google Scholar Reichart et al2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar associate the demise of 2 baboon recipients with the presence of pCMV in in cardiac xenografts, but the paper provides no evidence that pCMV was transmitted to the recipients or directly caused multiorgan failure that forced termination of the experiments. Perhaps a yet unidentified organism harbored by the baboons compromised innate immune control of pCMV. Regardless, pCMV will be excluded from potential sources of xenografts and since pCMV has not been shown to infect humans, Reichart et al2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar’s experience might reflect an instance in which non-human primates misrepresent a biologic barrier. In 2018, Längin et al3Längin M Mayr T Reichart B et al.Consistent success in life-supporting porcine cardiac xenotransplantation.Nature. 2018; 564: 430-433Crossref PubMed Scopus (142) Google Scholar called the first 4 successful orthotopic cardiac xenografts in baboons a milestone. If those xenografts and the 2 successful xenografts now reported2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar are a milestone, it is because they erase serious doubt about whether a porcine heart can survive and function for months in a non-human primate recipient receiving a clinically acceptable (if not yet optimal) immunosuppression regimen. But, the experiments do not prove clinical xenotransplantation will succeed—only clinical xenotransplants can prove that. If this regimen were used successfully in clinical xenotransplants, the clinical xenotransplants would be appropriately called a milestone, if the regimen failed some other term might be used. Reichart et al2Reichart B, Längin M, Radan J, et al. Pig-to-non-human primate heart transplantation: the final step toward clinical xenotransplantation [e-pub ahead of print]?J Heart Lung Transplant, https://doi.org/10.1016/j.healun.2020.05.004. Accessed July 6, 2020.Google Scholar’s report brings into focus an impending watershed in management heart failure. When clinical trials in cardiac xenotransplantation do begin, whether soon or after many more experiments, interest in the multitude of pre-clinical experiments and committee deliberations concerning the feasibility of xenotransplantation will fade. And, the central question will be whether the essential but intrusive immune modifiers and/or the less than optimal genetic background of engineered pigs8Platt JL Cascalho M Piedrahita JA Xenotransplantation: progress along paths uncertain from models to application.ILAR J. 2018; 59: 286-308Crossref PubMed Scopus (5) Google Scholar can be omitted or changed so that xenotransplantation can approach or even surpass the safety and efficacy of allotransplantation and become the preferred treatment for organ failure. That shift in focus as difficult to imagine as it may be will fuel identification and surmounting of barriers unapparent in today's pre-clinical models. If this impending change in interest in xenotransplantation seems fanciful, it just recapitulates how interest in allotransplantation changed 60 years ago. The authors have no conflicts of interest to declare. The work be the authors pertinent to this communication was supported by the National Institutes of Health (AI122369; OD023138) Pig-to-non-human primate heart transplantation: The final step toward clinical xenotransplantation?The Journal of Heart and Lung TransplantationVol. 39Issue 8PreviewThe demand for donated human hearts far exceeds the number available. Xenotransplantation of genetically modified porcine organs provides an alternative. In 2000, an Advisory Board of the International Society for Heart and Lung Transplantation set the benchmark for commencing clinical cardiac xenotransplantation as consistent 60% survival of non-human primates after life-supporting porcine heart transplantations. Recently, we reported the stepwise optimization of pig-to-baboon orthotopic cardiac xenotransplantation finally resulting in consistent success, with 4 recipients surviving 90 (n = 2), 182, and 195 days. Full-Text PDF