Treatment of hematological malignancies with T cell redirected bispecific antibodies: current status and future needs

ABSTRACT

Introduction: Enthusiasm for developing therapeutic bispecific antibodies (BsAbs) for cancer applications has become intense in the past decade facilitated by advances in molecular biology, hybridoma technology, and protein engineering. The central strategy in BsAb engineering is to combine the specificities directed at effector cells, and at a tumor target associated antigen (TAA) into a single construct.

Areas covered: This article highlights the clinical use of BsAbs to target effector cells to multiple myeloma (MM), non-Hodgkin lymphoma (NHL), acute myeloid leukemia (AML), and acute lymphoblastic leukemia (ALL). We discuss the successes, challenges, and future strategies. Secondary literature search was performed using Pubmed, clinicaltrials.gov and non-proprietary internet search engines.

Expert opinion: The use of BsAb constructs to target hematologic malignancies has achieved limited success to date. There continues to be a high level of enthusiasm for developing and applying new constructs to overcome the challenges in engineering and clinical application for hematologic malignancies.

KEYWORDS:

• Bispecific
• antibody
• hematologic
• malignancies
• AML
• Multiple myeloma
• ALL
• NHL

Article highlights

• Blinatumomab has shown the value of BsAbs in the treatment of ALL and has energized clinical investigation of BsAbs for the treatment of other hematologic malignancies

• The application of BsAbs appears most promising for AML and offers hope for patients refractory to standard chemotoxic agents

• The incorporation of BsAbs into the treatment paradigms for lymphoma and myeloma will face greater challenges amid a crowded market of well tolerated oral non-chemotherapeutic alternatives

• The various BsAb platforms each comes with certain advantages and disadvantages, in terms of dosing and administration, side effects (particularly cytokine release syndrome) and off-target toxicities

• The BsAb platform shows potential to engage other immune effector cells such as CD47 and NK cells and work synergistically with other immune targeted therapies as seen with the CiTE technology

• If BsAbs or BsAb used to arm T cells can be used to target hematologic malignancies without dose limiting toxicities, there would be significant clinical benefits attained by this approach

This box summarizes key points contained in the article.

Acknowledgments

We thank Taylor Matousek for the preparation of the figures and her editorial assistance. The authors acknowledge the patients for their participation in clinical trials and the efforts of medical, research, and nursing staff who have made contributions to the immunotherapy program.

Declaration of interest

LG Lum is co-founder of Transtarget, Inc. and serves on the scientific advisory board of Rapa Therapeutics. LG Lum has been supported in part by R01 CA 182526, R01 CA 092344, R01 CA 140314, Gateway for Cancer Research, Endowed Marion McNulty Weaver and Malvin C. Weaver Professor of Oncology Chair, funding University of Virginia Cancer Center P30CA044579, University of Virginia Strategic Investment Fund. L Foster does not have any conflicts of interest to declare. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer Disclosures

Peer reviewers on this manuscript have no relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.