The PhD work of Anke Janssen (UMC Utrecht) demonstrates that γδ T cells can play a crucial role in the first months after a stem cell transplantation by reducing the risk of viral reactivation.
γδ T cells are among the first immune cells to recover after a donor stem cell transplantation (SCT). SCT still remains the only curative treatment for various hematological malignancies, but is often complicated by infections, relapses and graft versus host disease (GVHD), a severe inflammatory reaction in organs of the recipient. T cells play a crucial role in both the efficacy of the treatment as well as the severe complications such as GVHD. Whereas αβ T cells are extensively studied after SCT, the role of γδ T cells is less clear. In the PhD thesis by Anke Janssen, MD (Department of Hematology and Center for Translational Immunology, UMC Utrecht) the role of γδ T cells after SCT is explored and their potential for therapeutic interventions is investigated.
Crucial role
GVHD after a donor SCT is mainly driven by αβ T cells. By depletion of the graft of αβ T cells to reduce the incidence of GVHD, while retaining the γδ T cells to control viral reactivations less complications after SCT were expected. In a multicenter, prospective Phase 1/2 clinical study in 35 adults, Anke Janssen and co-workers showed a favorable outcome with indeed less GVHD after αβ T cell depleted SCT. In depth analyses of the immune system after αβ T cell depleted SCT in the context of viral reactivations such as cytomegalovirus (CMV) and Epstein-Barr virus (EBV) showed the differences in reconstitution of the αβ- and γδ T cells. In the abcense of sufficient numbers and diversity of αβ T cells, γδ T cells played a crucial role in reducing the risk of viral reactivation during the first months after SCT.
Novel receptor
In the second part of this thesis the investigators identified novel tumor reactive γδ T cell receptors against a variety of cancer types. These receptors are tested in the TEG (αβ T cells engineered to express a defined γδTCR) concept and are interesting leads for future γδ T cell based immune effector cell therapies. For example, TEG001 (developed at UMC Utrecht and currently under investigation in a phase I clinical trial), which expresses a specific γ9δ2 T cell receptor that – in preclinical studies – has a proven high affinity and activity against various cancer types.
“My PhD research shows that γδ T cells play a crucial role in immune reconstitution after stem cell therapy, in particular in platforms where αβ T cells are depleted. As a result of the activity of γδ T cells against (viral) infections as well as against tumors are treatment strategies based on γδ T cell receptors a promising option for future immune therapies.”
PhD defense
Anke Janssen, MD (1985, Tilburg) defended her PhD thesis on December 3, 2024 at Utrecht University. The title of her thesis was “Rebuilding a repertoire; reconstitution of γδ T cells after allogenic stem cell transplantation”. Supervisor was prof. Jürgen Kuball, MD, PhD (Center for Translational Immunology and Department of Hematology, UMC Utrecht). Co-supervisors were Moniek de Witte, MD, PhD (Department of Hematology, UMC Utrecht) and Dennis Beringer, PhD (Center for Translational Immunology, UMC Utrecht). Anke Janssen works as an internist-hematologist at UMC Utrecht.
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February 19, 2024:
Engineering the next-generation of T cell-based cancer immunotherapies
