In 2018, Lucile Packard Children’s Hospital (LPCH) at Stanford welcomed two siblings with Schimke immuno-osseous dysplasia (SIOD), an extremely rare form of dwarfism that affects just seven children in the U.S. The two siblings, Kruz and Paizlee Davenport, are the first brother and sister pair with SIOD in the country to become ambassadors for the condition.
“There was a one in 80 million chance both Kruz and Paizlee would have SIOD,” says their mother, Jessica. Today the siblings are both being treated at LPCH, where they are receiving a ground-breaking treatment combining stem cell and kidney transplant from their HLA-partially matched parents. This innovative approach, which eliminates the use of post-transplant immunosuppressive drugs, is being overseen by a multidisciplinary team led by the author.
Children with SIOD have a life expectancy of 11 years and normally experience conditions such as kidney failure, severe T-cell deficiency, and hip dysplasia. So far, only five patients in the world have been reported to receive both a stem cell and kidney transplant. Four patients died because of post-transplant complications including severe graft-versus-host disease (GvHD). The fifth patient, Kruz, has fully recovered from a living donor kidney transplant that took place in July 2019, five months after the stem cell transplant where his mother Jessica was the donor. Paizlee, the younger sister, is now three months out of a paternal stem cell transplant and will receive the kidney from the father early next year.
These siblings are benefiting from a method of graft engineering pioneered by the author that makes it safer to receive stem cells from a donor who does not have an exact HLA match. In fact, to overcome the mismatch between donor and recipient, a novel method of ex vivo T- and B-cell depletion based on the selective elimination of αβ+ T cells (the lymphocyte subset responsible for GvHD occurrence) was implemented. After this manipulation, the graft contains not only hematopoietic stem cells (i.e. CD34+ cells), but also large numbers of effector cells such as Natural Killer (NK) cells and gd T cells. These lymphocyte’s subsets, promptly available after the transplants infusion, can effectively control severe infections and leukaemia recurrence. Using this graft manipulation’s strategy, the extensive depletion of αβ+ T cells (up to 5 logs) abrogates the risk of severe GvHD.
Thanks to this approach, a donor is virtually available for every patient in the need of a transplant. A fully matched related donor (sibling), is present in the family for only 25 per cent of the patients, and less than the remaining 60 per cent can allocate a suitable unrelated donor in an acceptable frame time. The likelihood of finding an optimal donor, varies among racial and ethnic groups, with the probability of identifying an appropriate donor being highest among whites of European descent (75 per cent) and lowest among blacks of South or Central American descent (16 per cent). Thus, there is an urgent clinical need for more broadly applicable hematopoietic stem cell transplant (HSCT) methods that can reach a wider range of patients. Such a development has a major medical impact in patients lacking a fully matched donor, a situation that is especially true for ethnic minorities.
However, this is not only a donor’s matter. The fast and robust neutrophil and platelet engraftment (13 and 11 days, respectively), the absence of the need of post-transplant pharmacological GvHD prophylaxis as well as the negligible risk of chronic GvHD, render this approach ideal for indications previously not for candidates for transplant due to the high burden of complications. SIOD is just one of the multiple different diseases that now can be treated with an αβ haplo-HSCT. Remarkably , the exciting result of this pilot experience combining stem cell and kidney transplantation from the same donor, has laid the foundation at Lucile Packard Children’s Hospital for expanding the use of αβ haplo-HSCT to diseases routinely not for candidates for allogeneic HSCT, to patients in very poor clinical condition and in the need of living donor solid organ transplant.