Allogeneic hematopoietic cell transplantation (HCT) remains a therapeutic mainstay for most hematologic malignancies, particularly myeloid diseases such as myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) [1, 2]. According to recent Center for International Blood and Marrow Transplant Research (CIBMTR) data, the quantity of HCTs continues to increase on an annual basis, with 2019 seeing nearly 4,000 transplants per year in the U.S. alone [3]. In spite of the global disruption to travel during the COVID-19 pandemic, the number of HCTs remained relatively stable following the 2019 peak, a testament to the enormous team effort and dedication required for transplantation to happen. The team effort is a sum of commitment from donors and donor centers, the robust logistical network of the NMDP, and the expertise of transplant centers who continue to make HCT a successful therapy.
But the cellular therapy field continues to evolve, with specialized treatments based on gene therapy and chimeric antigen receptor (CAR) T-cell therapy recently emerging as novel modalities for specific indications [4]. Will these specialized treatments eventually become the mainstays of treatment and make standard hematopoietic cell transplantation obsolete? Time will tell, but it is likely that HCT will remain a staple of cellular therapy, including as a salvage treatment when other more specialized cellular therapies do not work. The reasons for this are complex, but generally speaking, HCT results in the reconstitution of immune effectors that are able to recognize multiple potential targets on tumor cells based on minor human leukocyte antigens (HLA) rather than a single target [5]. One of the challenges with HCT is that these potential targets may also be present on healthy tissues, resulting in the on-target off-tumor side effect known as graft-versus-host disease (GVHD).
The common thread among all cellular therapies is the graft-versus-tumor (GVT) effect. In the context of a chimeric antigen receptor that is known to have a specific target, the existence of this effect can be measured quite easily. But in hematopoietic cell transplantation, the GVT effect is more elusive to define as there is no clear measurable target. Even characterizing the cells that mediate GVT is a challenge, let alone the antigen(s) that these cells recognize on the tumor. Furthermore, unlike with targeted cellular therapy whereby the GVT occurs when the product is infused, in HCT it may be dependent on immune effector cells that develop from donor stem cells and may not occur for many months after the transplantation. As a transplant provider, I see it all the time – tapering immune suppression several months following HCT may result in a measurable increase in the proportion of donor cells in the bone marrow and eradication of any persistent disease. Additional supportive evidence for the existence of GVT is the correlation between development of chronic GVHD and a lower incidence of relapse [5]. This suggests that the same phenomenon that mediates GVHD, if present at a controllable level, might also mediate GVT. This is what makes HCT curative, even though it is not yet possible to predict ahead of time whether GVT mediated by a particular donor’s immune effector cells will occur against a particular disease.
According to CIBMTR data, while the outcomes of transplantation have been improving over time because of a reduced incidence of non-relapse mortality, the incidence of disease relapse following hematopoietic cell transplantation has remained stubbornly persistent [3]. This may be in part a reflection of transplanting more patients who have more aggressive and refractory disease biology. But this could also reflect the possibility that, in spite of innumerable improvements in tipping the scale in favor of improved outcomes by reducing HCT complications, there has only been limited improvement in enhancing the graft-versus-tumor effect. Donor lymphocyte infusion (DLI) was among the first interventions following HCT that enhanced GVT and is a standard of care therapy to treat relapse but has limited efficacy and comes at a significant risk of graft-versus-host disease [6]. Most other interventions following HCT that aim to enhance GVT remain experimental.
So how do we enhance graft-versus-tumor without concurrently increasing the risk of graft-versus-host disease? There is no one right answer, but one approach is to use natural killer (NK) cells: members of the innate immune system with the capacity for direct anti-tumor cytotoxicity, the ability to recruit and activate other immune effector cells at the site of disease, and no known association with GVHD [7]. Advances in NK cell expansion methods have made adoptive transfer of these cells translatable to the clinical setting, and further improvement in their persistence and function following infusion have made this immunotherapy platform highly attractive [8]. At Dana-Farber Cancer Institute, the cytokine-induced memory-like (CIML) NK cell immunotherapy platform exhibited massive expansion after infusion into patients, tumor trafficking, recruitment of other immune effector cells to the tumor site, long-term persistence, and association with attainment of myeloid disease remission after hematopoietic cell transplantation relapse [9]. Its use has now expanded to multiple clinical trials in both the liquid and solid tumor settings [7]. A new Phase 1 clinical trial aims to capitalize on the advantages of this platform early after HCT to eradicate measurable residual disease, enhance early GVT, and hopefully prevent disease relapse (clinicaltrials.gov ID: NCT06138587).
