Immunology of allogeneic hematopoietic cell transplantation
Introduction
Allogeneic hematopoietic cell transplantation (HCT) is often performed to prevent relapse of hematologic malignancies such as acute myeloid leukemia (AML). It is effective when donor immune cells mount an effective immune response against residual tumor cells of the patient, also referred to as graft versus leukemia (GvL) response. Donor immune cells can however turn against healthy tissues of the stem cell recipient, resulting in - often devastating - graft versus host disease (GvHD). In fact, about 10-30% of allogeneic HCT recipients succumb to transplantation-related complications, of which GvHD and opportunistic infections are the most important. There is therefore a high unmet medical need to improve the safety of allogeneic HCT without compromising its strong immunotherapeutic GvL effects. Research in our group is focussed towards:
1. improving our fundamental understanding of GvL and GvH immunology
2. the development of novel therapies to prevent and treat AML relapse and GvHD
Highlights
Taking advantage of the strong immune responses allogeneic HCT patients can generate against their malignancies, we identified AML specific antibodies that have great potential as therapeutic antibodies. Target identification of these antibodies revealed a number of unexpected, novel targets such as the U5 snRNP200 complex and CD43s that are both expressed widely on AML blasts. Antibodies against these targets are cytotoxic by nature, are effective via antibody dependent cellular cytotoxicity (ADCC) or via complement dependent cytotoxicity (CDC). In addition, we created T cell engaging derivates of the antibodies that were effective against AML in vitro and in vivo. Further understanding of the biology and mechanism of action of these antibodies will provide a platform for their development into a product that can be applied in the clinic.
In parallel, we are working towards a better understanding of the immunological processes underlying the emergence and clinical behaviour of GvHD. GvHD is often ignited by tissue damage through radiotherapy, chemotherapy, infections and microbiome damage. We choose to focus on the tissue healing capacities of immune cells such as innate lymphoid cells (ILC). ILC are important mediators of epithelial tissue homeostasis that in addition have immunosuppressive properties. Patients with swift recovery of ILC after chemotherapy and after allogeneic HCT are less prone to develop GvHD. We are currently investigating means to enhance ILC recovery as a way to prevent mucositis and GvHD.
Funding
- PPOC (internal funding in competition)
- LSBR (Landsteiner Foundation)
- NWO ZonMW VIDI
- KWF Dutch Cancer Society
- AMC Foundation
