New antibody approaches to lymphoma therapy

Abstract

The CD20-directed monoclonal antibody rituximab established a new era in lymphoma therapy. Since then other epitopes on the lymphoma surface have been identified as potential targets for monoclonal antibodies (mAb). While most mAbs eliminate lymphoma cells mainly by antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity or direct cell death, others counter mechanisms utilized by malignant cells to evade immune surveillance. Expression of PD-L1 on malignant or stromal cells in the tumor environment for example leads to T-cell anergy. Targeting either PD-1 or PD-L1 via mAbs can indirectly eliminate cancer cells by unblocking the host intrinsic immune response. Yet another mechanism of targeted therapy with mAbs are bi-specific T-cell engagers (BiTE) such as blinatumomab, which directly engages the host immune cells. These examples highlight the broad spectrum of available therapies targeting the lymphoma surface with mAbs utilizing both passive and active immune pathways. Many of these agents have already demonstrated significant activity in clinical trials. In this review we will focus on novel CD20-directed antibodies as well as mAbs directed against newer targets like CD19, CD22, CD40, CD52 and CCR4. In addition we will review mAbs unblocking immune checkpoints and the BiTE blinatumomab. Given the success of mAbs and the expansion in active and passive immunotherapies, these agents will play an increasing role in the treatment of lymphomas.

Figure 1

Lymphoma cell surface targets for immunotherapy. Abbreviations: BiTE, Bispecific T-cell Engager; CCR4, C-C Chemokine Receptor Type 4.

Figure 2

Mechanism of pidilizumab, which increases T cell activation and cytokine release by inhibiting co-inhibitory signaling up-regulated by tumors. Abbreviations: MHC Major Histocompatibility Complex; TCR, T-cell Receptor; PDL-1, Programmed Death Ligand 1; PD-1, Programmed Cell Death Protein 1.

Figure 3

The bispecific T-cell engager blinatumomab targeting CD-19. Abbreviations: VL: variable region light chain; VH: variable region heavy chain.