Tom van Meerten
dr.
I am a hematologist involved in patient care, clinical and translation research in the field of malignant lymphoma. I focus on translational medicine on diffuse large B cell lymphoma and mantle cell lymphoma. My question by all our findings: how does the patient profit or does it help me to treat the patients. The focus of my research group is on DNA repair, cell cycle and cell death. We test novel combinations of existing anti-cancer agents to ultimately improve the treatment of patients suffering from lymphoma. I participate in the organization of new clinical trials both international (European Mantle cell Lymphoma Network) and national (HOVON). Moreover, I am actively involved in clinical trials concerning the application of CAR T cells for patient with lymphoma.
BH3 profiling to optimize lymphoma treatment: Pre-clinical studies
Unfortunately, lymphoma (Hodgkin’s and Non-Hodgkin’s lymphoma) is still an incurable disease for many people and new and smart treatment techniques are needed to improve the prognosis of these patients.
The goal of the research described in this dissertation was to find pre-existing medications used in other cancers, using a technique that allows to test the dependence on anti-apoptotic proteins (proteins important for the survival of cancer cells). This technique is called BH3 profiling.
By applying this technique, it has been found that tamoxifen, an affordable, anti-hormone drug that has been used in breast cancer for more than 40 years, can kill lymph node cancer cells in laboratory experiments and in animal experimental models. If tamoxifen is combined with a drug that blocks anti-apoptotic proteins, the anticancer effect is enhanced. This has led to a clinical trial in patients with untreatable aggressive lymphoma.
In addition to these important findings and applications, this thesis describes the efficacy of combinations of different drugs in lymphoma and whether these agents alter the dependence on these anti-apoptotic agents.
This project was carried out through a KWF grant.
The goal of the research described in this dissertation was to find pre-existing medications used in other cancers, using a technique that allows to test the dependence on anti-apoptotic proteins (proteins important for the survival of cancer cells). This technique is called BH3 profiling.
By applying this technique, it has been found that tamoxifen, an affordable, anti-hormone drug that has been used in breast cancer for more than 40 years, can kill lymph node cancer cells in laboratory experiments and in animal experimental models. If tamoxifen is combined with a drug that blocks anti-apoptotic proteins, the anticancer effect is enhanced. This has led to a clinical trial in patients with untreatable aggressive lymphoma.
In addition to these important findings and applications, this thesis describes the efficacy of combinations of different drugs in lymphoma and whether these agents alter the dependence on these anti-apoptotic agents.
This project was carried out through a KWF grant.
Myra Langendonk
Innate immune checkpoint inhibitors for treatment of Diffuse Large B-cell Lymphoma
Treatment of diffuse large B-cell lymphoma (DLBCL) with so-called innate immune checkpoint inhibitors is a novel immunotherapeutic treatment strategy that holds great promise for the future. In brief, this type of treatment reactivates phagocytes, important initiators of anticancer immunity. However, several issues remain to be addressed in order to optimally exploit checkpoint targeting for treatment of DLBCL. Within this thesis several of those issues are discussed.
The most prominent therapeutic target for innate checkpoint inhibitors today is the CD47-SIRPα axis. However, most of the clinically evaluated checkpoint inhibitors targeting this axis, are not tumor selective. In this thesis we discuss several improvements, e.g. tumor selective strategies, combinatory strategies and we designed fusion proteins that inhibit the CD47-SIRPα axis selectively on cancer cells. Next, we identified that high CD47 expression only associates with worse survival in non-germinal center B-cell (GCB) DLBCL patients, one of the two major subtypes of this disease. This implies that maybe not all DLBCL patients are suitable for CD47 blockade. Indeed, lab studies confirmed that only non-GCB cells responded to CD47 checkpoint inhibition. Notably, in contrast to earlier reports we identified that a positive phagocytic signal, SLAMF7, was not a requisite for effective treatment with CD47 checkpoint inhibitors and thus cannot be used to stratify patients for treatment. Finally, we describe a novel innate checkpoint, called CD300a, that may be of therapeutic interest for non-GCB DLBCL patients.
Taken together, this thesis describes strategies to improve checkpoint inhibitors targeting the CD47-SIRPα axis, highlights the importance of patient selection and identified a novel innate checkpoint with therapeutic potential for the treatment of non-GCB DLBCL. Finally, we point out that SLAMF7 should not be used as an inclusion criteria for treatment with CD47 blockade.
The most prominent therapeutic target for innate checkpoint inhibitors today is the CD47-SIRPα axis. However, most of the clinically evaluated checkpoint inhibitors targeting this axis, are not tumor selective. In this thesis we discuss several improvements, e.g. tumor selective strategies, combinatory strategies and we designed fusion proteins that inhibit the CD47-SIRPα axis selectively on cancer cells. Next, we identified that high CD47 expression only associates with worse survival in non-germinal center B-cell (GCB) DLBCL patients, one of the two major subtypes of this disease. This implies that maybe not all DLBCL patients are suitable for CD47 blockade. Indeed, lab studies confirmed that only non-GCB cells responded to CD47 checkpoint inhibition. Notably, in contrast to earlier reports we identified that a positive phagocytic signal, SLAMF7, was not a requisite for effective treatment with CD47 checkpoint inhibitors and thus cannot be used to stratify patients for treatment. Finally, we describe a novel innate checkpoint, called CD300a, that may be of therapeutic interest for non-GCB DLBCL patients.
Taken together, this thesis describes strategies to improve checkpoint inhibitors targeting the CD47-SIRPα axis, highlights the importance of patient selection and identified a novel innate checkpoint with therapeutic potential for the treatment of non-GCB DLBCL. Finally, we point out that SLAMF7 should not be used as an inclusion criteria for treatment with CD47 blockade.
Renée Bouwstra
Targeting WEE1 in diffuse large B-cell lymphoma: mediator in DNA damage and apoptosis
Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive type of non-Hodgkin lymphoma. The current treatment for the disease currently cures only 60% of the patients, which means new therapies are needed to improve patient survival. In this project, we performed a large gene expression analysis in 1800 DLBCL patient samples to find new targets to improve the current treatment. Here we found high expression of the WEE1 protein, which is involved in cell cycle regulation and repair of DNA damage. Inhibition of the WEE1 protein in DLBCL cell lines induced disruption of the normal cell cycle and high levels of DNA damage, eventually causing cell death. In addition, WEE1 inhibition showed to enhance the currently used therapies for the treatment of DLBCL, which include rituximab (anti-CD20), radiation, CHOP (first line chemotherapy) and cytarabine (second line chemotherapy). Based on these findings, we also investigated the effect of WEE1 inhibition in combination with so-called “anti-apoptotic inhibitors”, which prevent cells from protecting themselves against cell death. These inhibitors are currently being tested in clinical trials for different types of non-Hodgkin lymphoma and leukemia’s, including DLBCL . We found that WEE1 inhibition worked very well together with the anti-apoptotic inhibitors, and that combination therapy significantly enhanced cell death in DLBCL. In total, our results demonstrate that inhibition of WEE1 is very successful in DLBCL, and would likely improve the current treatment available for DLBCL.
Mathilde de Jong