Lenalidomide synergistically boosts CD1d-Vδ2 bispecific antibody-engaged Vγ9Vδ2-T cell anti-tumor functions via CD28, Notch, and IL-2.

Vγ9Vδ2-T cells are a unique T-cell subset with potent intrinsic antitumor activity against diverse cancer types, independent of the major histocompatibility complex. Despite their promise, harnessing their full potential, especially in challenging hematological malignancies like multiple myeloma (MM), acute myeloid leukemia (AML), and myelodysplastic syndromes (MDS), remains a significant challenge. Previous research demonstrated a bispecific T-cell engager (bsTCE) targeting CD1d and the Vδ2-TCR could engage Vγ9Vδ2-T cells against these cancers. This study explores whether existing standard-of-care drugs can enhance this bsTCE's efficacy, addressing a critical gap in optimizing Vγ9Vδ2-T cell-based immunotherapies.

Researchers evaluated various standard-of-care drugs for MM, AML, and MDS for their effects on CD1d-Vδ2 bsTCE-induced Vγ9Vδ2-T cell-mediated tumor cell lysis in vitro. Based on observed synergy, the immunomodulatory drug (IMiD) lenalidomide was selected for detailed investigation. Its impact on Vγ9Vδ2-T cell proliferation, phenotype, cytokine profile, and cytolytic activity was assessed using healthy donor peripheral blood mononuclear cells (PBMC) and PBMC and bone marrow samples from MDS patients. The study also explored lenalidomide's mechanism of action, focusing on intracellular signaling pathways.

Lenalidomide demonstrated significant synergistic activity with CD1d-Vδ2 bsTCE in enhancing Vγ9Vδ2-T cell antitumor responses. It substantially improved CD1d-Vδ2 bsTCE-induced Vγ9Vδ2-T cell activation, degranulation, and Th1-type cytokine secretion. Furthermore, lenalidomide promoted robust Vγ9Vδ2-T cell expansion. Mechanistically, these stimulatory effects were mediated through enhanced intracellular CD28 phosphorylation, activation of Notch signaling, and increased interleukin-2 (IL-2) release. This combination was particularly impactful in patient-derived samples:

Lenalidomide facilitated otherwise absent proliferation of Vγ9Vδ2-T cells with oncolytic potential in response to CD1d-Vδ2 bsTCE exposure in MDS patient-derived bone marrow samples, highlighting its critical role in overcoming resistance to expansion. These findings underscore a potent immunomodulatory effect of lenalidomide, significantly boosting the therapeutic potential of Vγ9Vδ2-T cell engagement.