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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13045-014-0058-4) contains supplementary material, which is available to authorized users.

Advances in the diagnosis and control of lymphomas

“…Currently, the most promising agents are direct inhibitors of anti-apoptotic family members, including BCL2, BCLXL, BCLw and MCL. 8 Currently, ABT-199, with a higher specificity for BCL2 and BCLXL, showed activity in relapsed/refractory lymphomas.…”

“…9,10 Thereafter, obinutuzumab (GA101) which represents a type II mAb increased ADCC and direct apoptosis both in vitro and in vivo, 11 and in 2013 was approved by FDA for untreated Chronic lymphocytic leukemia, however this antibody has been tested for aggressive B-cell NHL, as well as DLBCL and MCL, with promising results. 8,12 Other epitopes in CD20 antigen have also been targeted and ofatumumab has been tested in indolent and agressive NHL as single agent or combined with chemotherapy.…”

“…16 CD19 acts as a co-stimulatory molecule for B-cell receptor signaling. 8 MEDI-551 is an afucosylated antihuman CD19 mAb with a response rate of 24% in heavily pre-treated DLBCL an FL in phase I-II trials.…”

Immuno-PET Imaging of CD30-Positive Lymphoma Using 89Zr-Desferrioxamine–Labeled CD30-Specific AC-10 Antibody

“…However, in the era of antibody-based molecular therapies, immuno-PET is becoming an increasingly attractive diagnostic tool for providing more specific information about disease distribution, staging, and treatment response. Antibody-based therapies and diagnostic agents for lymphomas have focused mostly on targeting CD20 (30). Well-established anti-CD20 agents include antibody-based therapy with rituximab, radioimmunotherapy with 90 Y-ibritumomab tiuxetan or 131 I-tositumomab, SPECT imaging with 111 Inibritumomab tiuxetan, and PET imaging with 89 Zr-rituximab (30)(31)(32).…”

Bone marrow stromal cells enhance the survival of chronic lymphocytic leukemia cells by regulating HES‑1 gene expression and H3K27me3 demethylation

“…The treatment of CLL has markedly changed in the past years with the regulatory approval of idelalisib and ibrutinib. In addition, other antibodies are likely to become widely available in the next few years (2,3). Over the past decade, the essential role of the tumor microenvironment in the survival and progression of CLL has become increasingly clear (4).…”