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.
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 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.