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About
We focus on deciphering mechanisms underlying immune dysfunction in cancer patient and development of novel therapeutic approaches to (re)establish immune-mediated tumor control.
Aims
- Decipher the mechanisms underlying immune dysfunction in cancer patients.
- Exploration and development of novel immunotherapeutic approaches to (re)establish immune-mediated tumor control in cancer patients.
- Extensive immunoprofiling and monitoring to assess responsiveness to immunotherapeutic treatment.
The immune system forms a powerful defense mechanism against foreign pathogens, but also against altered or damaged cells, including cancer cells. The key effector cells involved in anti-tumor immunity, the T cells and NK cells, are highly capable of recognizing and attacking tumor cells. Nevertheless, despite induction of anti-tumor immune responses and presence of memory T cells following conventional therapies, many cancer patients develop progressive/relapsed disease and eventually die. This may amongst others be attributed to: 1) insufficient tumor reduction by conventional therapies, 2) inadequate induction and/or longevity of tumor-reactive T and NK cells, 3) poor immune effector functionality. The last decade, a breakthrough has been accomplished in cancer treatment through the introduction of immunotherapeutic strategies, demonstrating the power of harnessing the immune system.
Yet, although impressive clinical responses are achieved, not all patients respond to such therapy and treatment may be accompanied by (severe) toxicity in healthy tissues. Therefore, it is important to unravel the mechanisms that define the (dys)functional state of tumor-reactive T and NK cell responses and inter-patient differences in response to (immunomodulatory) therapy. This serves as cornerstone for adjuvant immunotherapeutic approaches to further boost anti-tumor immunity. Thereby, intensive and expensive treatment of non-responding patients may be prevented, and tailored therapies may be provided to improve outcome in cancer patients. We apply high-end >25 color (spectral) flow cytometry panels and high-dimensional clustering algorithms to dissect the composition, magnitude, phenotype and functional status of tumor-reactive T and NK cells in depth in hemato-oncology patients. Notably, we use peptide/HLA-multimer technology to further zoom in on the actual tumor-specific T cells and assess their characteristics in detail. Furthermore, we apply advanced immunological assays to evaluate T and NK cell (dys)function and investigate their responsiveness to (novel) immunotherapeutic strategies, including checkpoint blocking antibodies, siRNA technology and dendritic cell vaccination. In this way, we found that increased co-expression of inhibitory molecules PD-1, TIGIT and KLRG1 on tumor-reactive T cells was associated with relapse after donor stem cell transplantation. Furthermore, we demonstrated that tumor-reactive T cell functionality could be effectively restored through immune checkpoint blockade (anti-PD-1, anti-BTLA). Moreover, we develop superior ‘designer’ dendritic cell vaccines through silencing the inhibitory PD-L1/L2 molecules, introducing IL-15(Rα) mRNA and via our innovative culture protocol to generate myeloid and plasmacytoid dendritic cell subsets from hematopoietic stem cells isolated from the donor stem cell graft. The safety, feasibility and potency of our DC vaccination strategies is investigated in in vitro and in vivo models, as well as in phase I/II clinical trials together with the department of Hematology.
By gaining further understanding in the mechanisms underlying immune (dys)function in cancer patients and through exploration and development of novel immunotherapeutic strategies, we aim to provide patients with adjuvant (personalized) treatment options that allow (re)establishment of effective immune-mediated tumor control.
