Abstract
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.
| Original language | English |
|---|---|
| Qualification | Doctor of Philosophy |
| Awarding Institution |
|
| Supervisors/Advisors |
|
| Award date | 21-Sept-2022 |
| Place of Publication | [Groningen] |
| Publisher | |
| DOIs | |
| Publication status | Published - 2022 |