Peter, now 15, has been a lifelong patient at Lucile Packard Children’s Hospital. He needed a heart transplant at the age of two, and suffered from chronic ear infections, a broken leg, repeated bouts of pneumonia, and a challenging genetic lung disorder (primary ciliary dyskinesia). At the age of eight, he developed a very rare cancer — angioimmunoblastic T-cell lymphoma.
Standard cancer treatments were not working on Peter’s lymphoma and he suffered multiple relapses. He needed a stem cell transplant but having already received a heart transplant made it more difficult to introduce another immune system from a separate donor. In 2017, Peter received an αβ haplo-HSCT from his mother.
Today—two years later—Peter’s a sophomore in high school who enjoys playing video games with friends, practicing for his driving test in parking lots, excelling at school, and thinking about his future career and personal interests. And for the first time, his lymphoma is on molecular remission.
Despite marked improvement in the treatment of children affected by haematological malignancies with chemotherapy, a significant proportion of patients still require HSCT. Haploidentical transplantation opens the possibility to offer this treatment to every child in need of an allograft lacking an HLA-matched sibling, a matched unrelated donor, or a suitable umbilical cord blood unit. However, early attempts at haploidentical HSCT in leukaemia patients were associated with high rates of graft rejection and GvHD, leading to high transplant-related mortality and, consequently, poor survival. In the last two decades, novel insights in transplant immunology, continuing advances in graft-manipulation technology, and improved supportive care strategies have led to significantly better outcomes, so that, with further refinements, it is possible that haplo-HSCT become the preferred transplant option for children with hematologic malignancies without an HLA-identical relative.
In order to remove T cells, responsible for GvHD, and B cells, from which post-transplant lymphoproliferative disease (PTLD) can arise, positive selection of CD34+ hematopoietic stem cells (HSCs) has been employed for many years in haplo-HSCT. Although the administration of CD34+ cell megadoses has been demonstrated to be a valid approach for preventing both graft failure and severe GvHD in haplo-HSCT recipients, removal of lymphoid cells and committed hematopoietic progenitors from the graft cause prolonged lymphopenia and delay immune reconstitution, resulting in an increased risk of non-relapse mortality (NRM), mainly from opportunistic infections. In order to circumvent this delay in immune recovery, in 2010, a more sophisticated method of graft manipulation based on selective depletion of ab T lymphocytes, and of B cells (ab haplo-HSCT) was developed. This refined technique of graft engineering reduces the problems associated with delayed immune recovery, which is typical in the CD34+ cell selection approach. Indeed, using ab haplo-HSCT, it is possible to transfer to the recipient not only donor hematopoietic stem cells but also committed hematopoietic progenitors, as well as mature NK and gd T cells.
These lymphocyte subsets may provide a protective effect against both leukaemia relapse and severe infections. Human gd T cells orchestrate both innate and adaptive immunity and, unlike ab T cells, recognise tumours in a MHC-independent manner without causing GvHD, giving them immense clinical appeal. Both NK and gd T cells exert a potent antileukemia effect able to prevent the risk of relapse after HSCT.
The author recently validated her single-centre results in a multi-centre setting, conducting a retrospective comparative analysis within 13 Italian centres. Evaluating 245 matched unrelated donor (MUD) and 98 ab haplo-HSCT recipients we demonstrated that: first, this approach is associated with a cumulative incidence of NRM and disease recurrence comparable to that of children transplanted from a fully MUD. Second, ab haplo-HSCT abrogates the risk of developing severe acute GvHD and is also associated with a faster neutrophil and platelet recovery than MUD-HSCT. Finally, when compared to a mismatched unrelated donor HSCT, αβ haplo-HSCT is clearly superior, showing a significantly lower NRM and a better chronic GvHD-free/relapse-free survival (GFRS).
In light of all these considerations, αβ haplo-HSCT represents the ideal platform for post-HSCT adoptive immunotherapy for treating either malignant or non-malignant disorders.
https://insights.omnia-health.com/laboratory/latest-developments-treating-siod