C. (Christianne) Groeneveldt, MSc, PhD

While immunotherapy is considered a promising approach for the treatment of different cancer types, success in pancreatic cancer is low. Using patient-derived organoids, we are investigating whether targeting the DNA Damage Response (DDR) pathway can increase the efficacy of immunotherapy for pancreatic cancer. Research has shown that defects in the DDR pathway, or the use of DNA repair inhibitors, can result in the accumulation of cytosolic DNA fragments. The presence of these cytosolic DNA fragments can be sensed by the cGAS/STING pathway, which drives type I interferon signaling. An increased type I interferon signaling might lead to enhanced activation of dendritic cells and improved priming of tumor-specific CD8⁺ T cells, and ultimately increase the efficacy of immunotherapeutic strategies (such as immune checkpoint blockade or DC vaccination therapy). We employ techniques such as flow cytometry, immunohistochemistry, qPCR, Western Blot, and RNAseq in both patient-derived organoids and cell lines. In a second research line, we are investigating the mechanisms underlying immune-related adverse events (irAEs) which are often observed in patients treated with immune checkpoint-blocking antibodies αPD1 and αCTLA-4. The ultimate goal is to develop strategies that minimize irAEs while maintaining antitumor efficacy. For this project, we make use of above-mentioned techniques and preclinical (genetic) mouse models for toxicity and anti-tumor efficacy.

Christianne Groeneveldt obtained her BSc (2016) and MSc (2018) degrees in Bio-Pharmaceutical Sciences at Leiden University. She subsequently started as a PhD student in the Department of Medical Oncology at the Leiden University Medical Center (LUMC) under the supervision of Prof. Sjoerd van der Burg, Prof. Thorbald van Hall, and Dr. Nadine van Montfoort. During her PhD, she studied how oncolytic reovirus can be employed to increase the efficacy of T-cell-based immunotherapy in preclinical models for pancreatic and colon cancer. After completion of her PhD (2023), Christianne joined the Department of Pulmonary Medicine at the Erasmus MC as a postdoctoral researcher where she continues to study various ways to enhance the efficacy of immunotherapy for pancreatic cancer patients.

Pancreatic tumors respond poorly to T-cell-based immunotherapy, which is often attributed to a lack of intratumoral T cells. We demonstrated that treatment with oncolytic reovirus allows specific infection and inflammation at the tumor site, which results in a fast and potent influx of T cells. These T cells could be activated by CD3-bispecific antibodies or checkpoint inhibitors, which resulted in potent antitumor responses. We also demonstrated that these combination therapies can be further enhanced by blockade of TGF-β signaling and that these therapies can still be effective when preexisting neutralizing antibodies are present (in around 80% of humans).