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Novel Cereblon-Binding Immunomodulators Have Increased Potency Against Gammaherpesvirus- Associated Lymphomas In
Prabha Shrestha1, Emma N Treco1, David A Davis1
1HIV and AIDS Malignancy Branch, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland, USA.
Newer cereblon-binding immunomodulators (CBIs), golcadomide and iberdomide, show greater effectiveness against aggressive lymphomas like primary effusion lymphoma (PEL) and Burkitt lymphoma (BL) compared to pomalidomide. These novel CBIs enhance immune cell recognition and are promising for clinical investigation.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Primary effusion lymphoma (PEL) and Burkitt lymphoma (BL) are aggressive non-Hodgkin's lymphomas with poor prognoses.
- Kaposi sarcoma herpesvirus (KSHV) causes PEL, while Epstein-Barr virus (EBV) is associated with a subset of BL.
- Cereblon-binding immunomodulators (CBIs), including pomalidomide (Pom), demonstrate efficacy against certain lymphomas.
Purpose of the Study:
- To evaluate the in vitro activity of next-generation CBIs, golcadomide (Golc) and iberdomide (Iber), against PEL and BL cell lines.
- To compare the potency of Golc and Iber with Pom in suppressing lymphoma cell growth.
- To investigate the mechanisms underlying the activity of novel CBIs, including effects on IRF4 and immune surface markers.
Main Methods:
- In vitro assessment of Golc and Iber activity against PEL and BL cell lines.
- Determination of half-maximal inhibitory concentrations (IC50) for growth suppression.
- Analysis of changes in interferon regulatory factor 4 (IRF4) expression and immune surface markers (ICAM-1, B7-2, MHC-I).
- Evaluation of CBI activity in pomalidomide-resistant cell lines with low cereblon levels.
Main Results:
- Golc and Iber demonstrated substantial growth suppression of PEL and BL cell lines at significantly lower IC50 values than Pom.
- Growth suppression was partly mediated by enhanced downregulation of IRF4 in PEL cells.
- Golc and Iber increased immune surface markers (ICAM-1, B7-2, MHC-I) at lower concentrations than Pom, enhancing T-cell recognition.
- Novel CBIs showed limited activity in pomalidomide-resistant cell lines, highlighting the importance of cereblon binding.
Conclusions:
- Next-generation CBIs, particularly Golc, are more potent and effective against PEL and BL cell lines than Pom.
- The enhanced efficacy is linked to increased cereblon affinity, IRF4 downregulation, and improved immune cell engagement.
- Novel CBIs represent a promising therapeutic avenue for patients with PEL and BL and warrant further clinical investigation.
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