Bispecific antibodies for the treatment of B-cell lymphoma: promises, unknowns, and opportunities

Abstract

Treatment paradigms for B-cell non-Hodgkin lymphomas (B-NHL) have shifted dramatically in the last 2 decades following the introduction of highly active immunotherapies such as rituximab. Since then, the field has continued to witness tremendous progress with the introduction of newer, more potent immunotherapeutics, including chimeric antigen receptor T-cell therapy, which have received regulatory approval for and currently play a significant role in the treatment of these diseases. Bispecific antibodies (BsAb) are a novel class of off-the-shelf T-cell redirecting drugs and are among the most promising immunotherapeutics for lymphoma today. BsAb may target various cell-surface antigens and exist in different formats. Anti-CD20xCD3 BsAb have demonstrated remarkable single-agent activity in patients with heavily pretreated B-NHL with a manageable toxicity profile dominated by T-cell overactivation syndromes. Much work remains to be done to define the optimal setting in which to deploy these drugs for B-NHL treatment, their ideal combination partners, strategies to minimize toxicity, and, perhaps most importantly, pharmacodynamic biomarkers of response and resistance. In this review, we provide an update on BsAb development in B-NHL, from discovery to clinical applications, highlighting the achievements, limitations, and future directions of the field.

Graphical abstract

Figure 1.

Mechanisms of resistance to BsAb within the lymphoma microenvironment. Potential mechanisms of resistance to BsAb therapy include (A) tumor cell–intrinsic mechanisms, such as antigen loss and activation of immune-evasive gene expression programs, (B) T-cell intrinsic mechanisms, including activation of regulatory T-cells, downregulation of the T-cell receptor, and development of T-cell exhaustion, and (C) T-cell extrinsic mechanisms, including recruitment of immunosuppressive myeloid and/or stromal cells. CAF, cancer-associated fibroblast; IL-10, interleukin-10; MDSC, myeloid-derived suppressor cell; PD-1, programmed death 1; PD-L1, programmed death ligand 1; TAM, tumor-associated macrophage; Teff, effector T cell; Texh, exhausted T cell; TGF-b, transforming growth factor beta; Tim-3, T-cell immunoglobulin mucin-3; Treg, regulatory T cell.