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Preclinical Study of Combination Therapy for CLL: Avadomide Plus Checkpoint Inhibition

By: Sarah Campen, PharmD
Posted: Thursday, March 11, 2021

Combining avadomide with anti–PD-L1 therapy may enhance activity against chronic lymphocytic leukemia (CLL), according to the results of a preclinical study published in Blood. A cereblon E3 ligase modulator, avadomide appears to induce interferon signaling in T cells, triggering a “feedforward cascade” of immune responses and increasing susceptibility to checkpoint inhibitors. “These data illustrate the importance of overcoming a low inflammatory T-cell state to successfully sensitize CLL to checkpoint blockade–based combination therapy,” stated Alan G. Ramsay, PhD, of King’s College London, United Kingdom, and colleagues.

In this study, immune-modeling assays indicated that avadomide stimulated T-cell activation, chemokine expression, motility, and lytic synapses with CLL cells. Avadomide also induced type I and II interferon signaling in patient T cells through the upregulation of PD-L1.

Patient-derived xenograft tumors treated with avadomide were converted to CD8-positive T cell–inflamed tumor microenvironments, which resulted in response to anti–PD-L1–based combination therapy.

Clinical analyses of pretreatment and early on-treatment peripheral blood samples from patients with relapsed or refractory CLL receiving avadomide-based therapy showed increased PD-L1 expression on T cells, as well as intratumoral expression of chemokine signaling genes. “Collectively, this preclinical study using CLL as a model B-cell malignancy provides proof of concept that inducing inflammatory interferon type I and II signaling in patient T cells can successfully reshape antitumor T-cell responses and sensitize CLL to immune checkpoint blockade,” the authors concluded.

Disclosure: For full disclosures of the study authors, visit ashpublications.org.



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