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About
We focus on the development of new, additional forms of cellular immunotherapy in (hematological) cancer patients through translational and (pre-)clinical research.
Research group leader
prof. dr. Harry Dolstra
Aims
- Development and clinical exploration of complementary immunotherapy after hematopoietic stem cell transplantation.
- Understanding interactions between NK cells, other immune cells and cancer.
- Development and introducing NK cell-based immunotherapy in cancer treatment.
- Development of stem cell memory CAR T cell therapy against hematological cancers.
Hematopoietic stem cell transplantation and immunotherapy are two important pillars in the clinical care of hematological cancer patients. The promise is that new forms of cellular immunotherapy become complementary or provide a bridge to donor stem cell transplantation, or perhaps make it unnecessary.
The Translational Immunohematology research group operates in the front line to develop these new, innovative cell therapies for (hematological) cancer patients, and focuses specifically on the following research lines:
Immunobiology of the graft-versus-tumor effect and complementary immunotherapy after hematopoietic stem cell transplantation.
During the past decade, a major research topic was the investigation which tumor antigens and immune cell populations (NK and T cells) are involved in the therapeutic graft-versus-tumor effect after allogeneic donor stem cell transplantation. By applying various molecular approaches, we and others discovered the molecular identity of an array of polymorphic tumor antigens that are targeted by donor T cells post-transplantation. These identified tumor antigens are currently exploited as targets in adjuvant vaccination strategies as well as adoptive cell therapy after stem cell transplantation. In addition, we have developed a culture protocol for generating early memory T cells using pharmacologic inhibition of the Akt-signaling pathway for adoptive immunotherapy purposes in hematological malignancies, which can be combined with vaccination. Furthermore, we investigate whether this culture protocol is applicable to generate T cell products modified with chimeric antigen receptors (CAR) to improve CAR-T cell therapy.
Natural Killer cells: immunobiology and immunotherapy.
Much knowledge has also been gained about the immunobiology of NK cells that play a role in the immune defense against cancer in the past decade. It has become known that NK cells are regulated by a balance of signals of inhibitory and activating receptors. Normally an NK cell is at rest because the signals from inhibitory receptors predominate. However, due to loss of these inhibitory signals (e.g. loss of MHC class I expression) or over-stimulation by activating signals in viral infections and tumors, NK cells can become highly activated and kill the aberrant cells. This makes NK cells attractive immune cells to exploit in the treatment of cancer, and clinical studies have found first indications that allogeneic donor NK cells have a therapeutic effect against acute myeloid leukemia. In recent years, we have developed innovative culture methods to generate hyperactive NK cells from hematopoietic stem cell sources (umbilical cord blood, bone marrow, mobilized donor blood). In a first-in-human clinical trial we reported that infusion of these ex vivo generated NK cells was feasible and well tolerated in patients with acute myeloid leukemia. Follow-up clinical studies are currently ongoing to investigate safety and therapeutic efficacy in chemotherapy-refractory or relapsed acute myeloid leukemia and ovarian cancer patients. In addition, preclinical research is being performed to test the efficacy of these ex vivo generated NK cells in combination with immunomodulating agents, checkpoint inhibitors or genetic modification with CARs and IL15/IL15Rα to improve in vivo tumor-targeting and persistence.
Chimeric antigen receptor (CAR) cell therapy against hematological malignancies.
Genetic engineering of immune effector cells with CARs is one of the latest immunotherapies that has shown successful results in certain hematological malignancies. This form of immunotherapy involves genetically modified autologous or allogeneic donor T or NK cells that recognize specific proteins on target cells and induce functional activity. These CAR-modified immune cells can more efficiently eliminate malignant tumor cells that carry these specific proteins on their surface. Recently, two CAR-T cell products have already been marketed for the treatment of chemotherapy-refractory acute lymphocytic leukemia and B cell lymphoma. Major challenges of CAR cell therapy are to control life-threatening side effects such as organ damage by the cytokine release syndrome and severe neurotoxicity. In addition, there is still room for improvement of the optimal culture conditions, differentiation stage (T / NK fitness), cell product composition and manufacturing conditions of CAR cell products to optimize safety and effectiveness in patients. Renewal of the CAR construct design is also needed for optimal signaling per cell type (NK versus T cells) and for targeting multiple specific proteins to prevent tumor escape through antigen loss. In addition, we will need to understand adaptive resistance mechanisms of CAR cell therapy to develop rational combinations with immunomodulating agents or checkpoint inhibitors to increase clinical efficacy. Our research focuses on the development of CAR cell therapy with the developed NK and T cell culture methods for the therapy of hematological malignancies.
