Breakthrough in Orthotopic Cardiac Xenotransplantation: In a Preclinical Life-Supporting Pig-To-Baboon Model Worldwide First Continuous Successful Long-Term Survival (Up To 172/187 Days, Both Ongoing)

 

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Introductions: After 25 years of experimental OHXTx of transgenic (tg) pig hearts we achieved in the past 2 years, a major breakthrough with a constant long-term survival of GalKO/CD46/hTM tg pig hearts with a new immunosuppression (IS) basing on CD40-Ab or CD40L-Ab costimulation blockade (CSB), secondary with an improved initial xenograft function by using a non-ischemic, cold perfusion for organ preservation and finally with a postoperative growth control.

Methods: Fifteen OHXTx were performed in baboons with GalKO/hCD46/hTM tg pig hearts. Basic IS consisted in a group 1 (G1, n = 5) of ATG, rituximab, MMF, cortisone and CSB with CD40Ab (mouse/rhesus, clone 2C10R4) or our own humanized PASylated Fab-CD40L (XL-protein/Wacker-Chemie). To prevent the so-called “perioperative cardiac xenograft dysfunction” (PCXD) as an early cardiac low output, observed with crystalloid cardioplegia (Bretschneider), we replaced it in a group 2 (G2, n = 6) with a non-ischemic cold perfusion technique (8 °C cold “Steens solution” with oxygenated blood). To inhibit pig xenograft growth and hypertrophy, in a group 3 (G3, n = 4), antihypertensive and anti-proliferative drugs were given.

Results: Survival in G1 with crystalloid cardioplegia were 1 (three times with PCXD), 3, and 30 day(s). In G2 with nonischemic cold preservation baboons survived 1, 3, 18, 27, 40, and 50 days (no PCXD). Baboons in G2 mostly died of liver and respiratory failure, primarily caused by a pig heart hypertrophy and diastolic LV failure. After treatment of this xenograft (over)growth in G3 all baboons were long-term surviving (two were actively terminated after 90 days according to the government guidelines) and two are ongoing on days 172 and 187 in excellent general conditions. No hyperacute or delayed xenograft (DXR) rejection was observed.

Conclusion: Because ISHLT advisory board guidelines from the year 2000 recommend a 90-day survival of minimal 60% (6 of 10 baboons) in a life-supporting pig-to-baboon model with treated DXR and compatible IS as preclinical efficacy requirements before starting clinical trials, this concept of group G3 with the new CSB IS regimes, cold perfusion preservation technique and treatment of pig hearts overgrowth resulting in a consistent, reproducible long-term survival of life-supporting orthotopic multi-tg pig hearts up to half a year is after 25 years of xenotransplantation research a major breakthrough and essential milestone on the way to clinical cardiac XT in the next years.