Dual Targeting Augments Anti-Lymphoma Activity in MCL

Dual targeting of Bruton tyrosine kinase (BTK) and ROR1 signaling pathways, using a combination of BTK inhibitors and zilovertamab, augmented anti-lymphoma activity in mantle cell lymphoma (MCL) models with TP53 mutations, according to a recent study.

The study, led by Lei Nie, MD, of the University of Texas MD Anderson Cancer Center, evaluated ROR1 expression levels in a panel of MCL cell lines and primary patient samples using flow cytometry and immunoblotting analysis. Dr. Nie and colleagues also used a patient-derived xenograft (PDX) mouse model to evaluate single-agent and combination efficacy of BTK inhibition plus zilovertamab.

Single-Agent Versus Combination Therapy in MCL Cell Lines

Compared with normal peripheral blood mononuclear cells (PBMCs), researchers detected ROR1 expression in all MCL cell lines, including JeKo-1, Mino, Z-138, Granta519, JVM2, SP49, Maver-1, and Rec-1. Researchers then examined the cytotoxic effect of BTK inhibition in combination with zilovertamab on MCL cell lines and found that:

• Treatment with a single BTK inhibitor at 2–10 µM (ibrutinib, zanubrutinib, acalabrutinib, or pirtobrutinib) significantly induced cytotoxicity in the TP53-mutatedMCL cells.
• MCL cell death significantly increased when a BTK inhibitor was combined with zilovertamab at 25-50 µg/ml.
• In MCL cell lines with wild-type TP53, BTK inhibition plus zilovertamab did not significantly increase the cytotoxic effect compared with single agents.

“These results suggest that the genetic status of TP53 is important for the augmented cytotoxic effect of [BTK inhibition and zilovertamab] combination on MCL cells,” the researchers wrote.

Effect of BTK Inhibition Plus Zilovertamab on PDO Models

Finally, researchers performed an ex vivo viability assay using patient-derived organoid (PDO) platform and found that BTK inhibition plus zilovertamab resulted in “potentiated cytotoxic activity” in the PDO models derived from both treatment-naïve and relapsed patients with TP53 mutations. Additionally, the combination demonstrated synergistic effect in a PDX model derived from a patient with TP53 mutations.

Reference

Nie L, Jiang V, Liu Y, et al. Dual targeting of ROR1 and BTK augments the anti-lymphoma activity in mantle cell lymphoma. Abstract #4366. Presented at the 65th ASH Annual Meeting and Exposition; December 9-12, 2023; San Diego, California.