Ian S. Jaffe is a member of the Xenotransplant Research Group at NYU Langone Health and an MD/MS trainee at the NYU Grossmans School of Medicine. His research is focused on human xenotransplant studies in decedent and living recipients.

 

Aprajita Mattoo, MD, is an Assistant Professor of Medicine at NYU Langone Transplant Institute with a research interest in xenotransplantation and novel therapeutic strategies for highly sensitized patients.

 

For decades, the field of xenotransplantation has been haunted by the joke, “xenotransplantation is the future…and always will be.” Remarkably, after a long and tumultuous history—including a near-reset of the field in the 1990s when the focus shifted from non-human primate donors to genetically engineered pigs—kidney xenotransplantation is finally on the cusp of becoming a clinical reality. Earlier this year, two patients received porcine kidney xenotransplants under single-patient compassionate use approvals from the FDA. Formal first-in-human clinical trials (FIHCTs) are expected to follow soon, with several developers of genetically modified porcine kidneys targeting next year as the start date. These important steps forward signal a revolutionary solution for the problem of organ shortage that plagues the field of transplantation and offers new hope to the approximately 100,000 patients awaiting a kidney transplant in the US and the more than 800,000 patients suffering from end-stage kidney disease. However, the road to xenotransplantation remains a difficult journey, requiring a delicate balance between potential benefits and significant risks.

A recent report by Adams et al. summarizes the discussions at the National Kidney Foundation’s (NKF) April 2022 Scientific Workshop on Xenotransplantation, which convened a diverse panel of experts, clinicians, and patient advocates to discuss the barriers and challenges of progressing to FIHCTs. The workshop underscores the immense complexity of xenotransplantation, where clinical and regulatory considerations often veer into uncharted territories. In addition to determining whether a porcine kidney xenograft can adequately replicate the full spectrum of human renal physiology (i.e., salt-water balance, acid-base and electrolyte homeostasis, hormone production, and drug/toxin excretion), a transplanted porcine kidney interfaces with the human immune system in unique and still not fully understood ways. It requires novel approaches to immunosuppression and carries both conventional and zoonotic infectious risks. These intertwined factors make the transition to human trials an exciting but daunting step.

Image from Pixabay / Thor_Deichmann

Immunologic challenges remain a central concern for first-in-human xenotransplantation trials. Identifying the optimal combination of genetic modifications and immunosuppressive therapies is an ongoing struggle for researchers. While the genetic knockout of the mammalian cell membrane carbohydrate galactose-1,3 α-galactose (α-Gal ) has become the minimum standard for porcine xenograft donors, additional genetic edits are still under evaluation. Additional uncertainty in this area stems from the fact that the human immune system may react differently to these porcine genetic modifications as compared to non-human primates (NHPs), particularly in terms of humoral responses to other carbohydrate antigen edits, thus limiting the utility of pre-clinical NHP studies in this area. Moreover, proper function of humanized transgenes may not necessarily be reliably extrapolated from evaluations in a third-party species. Finally, many immunosuppressive regimens that work in allotransplantation have not proven useful in primates. For instance, humanized transgenes like CD55 and CD59 may theoretically prevent complement activation, but their function could be rendered unnecessary by the use of clinical-grade complement inhibitors like eculizumab which does not work effectively in NHPs. Another major issue is the reliance on drugs targeting the CD40-CD154 pathway, which have been critical for prolonging graft survival in NHP models. Unfortunately, none of these drugs have passed clinical trials in humans due to complications like thrombotic events. While newer versions of these drugs are in early-phase human trials, their safety and efficacy remain uncertain. Given that many conventional immunosuppressive strategies and rescue treatments for allotransplants have not worked in primates, and successful immunomodulators in primates have failed in humans, the transition from NHPs to porcine xenotransplants to humans is not as straightforward as anticipated. These gaps highlight the need for careful, phased clinical trials to answer critical questions about the safety and effectiveness of both genetic modifications and immunosuppressive regimens of porcine xenografts.

Despite these challenges, the early single-patient human trials that have occurred since this workshop originally took place offer reasons for cautious optimism. Both the Massachusetts General Hospital (MGH) and New York University (NYU) Langone Health recently performed porcine  kidney xenotransplants under compassionate use approvals from the FDA, and while neither graft survived more than two months, neither hyperacute rejection nor accelerated humoral rejection were cited as the cause of failure in either case. In the MGH case, the patient’s death was reportedly unrelated to the xenotransplant, and in the NYU case, mechanical perfusion issues were the cited reason for graft failure (although findings from neither study have been peer reviewed and published at the time of this post). These cases are particularly noteworthy because they used different porcine xenograft genetic constructs and immunosuppressive regimens —highlighting the lack of consensus on the ideal approach in the field. MGH used a triple glycan knockout kidney with seven human transgenes (plus endogenous retrovirus knockouts) alongside CD40 inhibition with experimental tegoprubart and C5 inhibition with investigational revulizumab, while NYU used an α-Gal knockout kidney with C3 inhibition with off-label pegcetacoplan. The fact that neither regimen reportedly led to overt rejection within the several months- timeframe is reassuring. This is in stark contrast to early xenotransplant heart trials, where confirmed or suspected acute antibody-mediated rejection led to graft failure in a similar timeframe. However, the vastly disparate approaches used in these two studies highlights the persisting lack of agreement on genetic edits and immunosuppressive combinations, underscoring the need for further research and exploratory studies in the field. The NKF workshop participants appropriately emphasized the need for coordination in research efforts and mandatory outcome reporting to help consolidate knowledge from FIHCTs to improve future approaches. Importantly, the public and patient communities have shown a growing appetite for xenotransplantation. During a meeting with the FDA in November 2023 organized by the NKF, patients with end-stage kidney disease expressed a strong desire to participate in xenotransplant FIHCTs, despite the known risks. Many of these patients face a grim prognosis on dialysis and see xenotransplantation as their best chance for an improved quality of life. The NKF workshop participants proposed eligibility criteria for FIHCTs (see the box below), focusing on patients with low probability of receiving a traditional kidney transplant and a reasonable likelihood of surviving the xenotransplant procedure. These patients represent the cohort where clinical equipoise exists—balancing the significant risks of xenotransplantation with the potential for meaningful survival and quality-of-life benefits.

Box 5 from Adams et al, © National Kidney Foundation.

As we stand on the brink of first-in-human clinical trials for kidney xenotransplantation, the field must continue to proceed with cautious optimism. The results from recent NHP, human decedent, and single-patient trials offer some reassurance, but they also highlight the complex, incompletely resolved questions around immunosuppression, genetic modifications, and long-term graft survival. Moving forward, FIHCTs will provide invaluable insights that will shape the future of xenotransplantation, while offering hope to the many patients desperately searching for an option. Success will require coordination across the scientific, regulatory, and patient communities, with a commitment to transparency, patient safety, rigorous evaluation, and constant iterative improvements. While the path ahead will undoubtedly be challenging, providing the best future for our patients demands we take careful—even if uncertain—steps forward.