Novel Cereblon-Binding Immunomodulators Have Increased Potency Against Gammaherpesvirus- Associated Lymphomas In Vitro

Abstract

Primary effusion lymphoma (PEL), which is caused by Kaposi sarcoma herpesvirus (KSHV), and Burkitt lymphoma (BL), a subset of which are associated with Epstein-Barr virus (EBV), are aggressive non-Hodgkin's lymphomas. Both have relatively poor survival compared to other lymphomas. Cereblon-binding immunomodulators (CBIs), such as pomalidomide (Pom), show in vitro efficacy and clinical activity against certain of these lymphomas. Next generation CBIs, such as golcadomide (Golc) and iberdomide (Iber), have increased affinity to the primary cellular target, cereblon, making them potentially better anticancer agents. Here, we report the in vitro activity of these novel CBIs against PEL and BL cell lines. Both Golc and Iber, but primarily Golc, caused substantial growth suppression of PEL and BL lines with much lower half-maximal inhibitory concentration (IC₅₀) compared to Pom. This growth suppression was mediated, in part, by enhanced downregulation of interferon regulatory factor 4 (IRF4) in PEL cell lines. Additionally, both Golc and Iber increased immune surface markers such as ICAM-1, B7-2, and MHC-I in PEL and BL cells at lower concentrations than Pom; these increases led to enhanced recognition of both PEL and BL cells by T-cells. The novel CBIs had relatively little activity in Pom-resistant cell lines with low levels of cereblon, suggesting that binding to cereblon is also important for the functions of the novel CBIs. These data show that the newer CBIs are more potent and effective against PEL and BL lines than Pom, and therefore, are worth investigating clinically in patients with these tumors.