Bispecific antibodies in acute lymphoblastic leukemia therapy

ABSTRACT

Introduction

Blinatumomab, first in a class of bispecific T-cell engagers, revolutionized treatment paradigm of B-cell precursor relapsed/refractory or minimal residual disease positive acute lymphoblastic leukemia (ALL) in adults and children, inducing deep remissions in a proportion of patients. However, significant numbers of patients do not respond or eventually relapse. Strategies for improvement of treatment outcomes are required.

Areas covered

This review discusses the main structural and functional features of blinatumomab, and its place in the treatment of ALL. Furthermore, prospects to increase the efficacy of blinatumomab are addressed. The developments in the field of bispecific antibodies and their possible implications for treatment of ALL are reviewed.

Expert opinion

Better understanding the mechanisms of response and resistance to blinatumomab might help us to identify the group of patients benefiting most from treatment and to spare potentially toxic subsequent treatment strategies. Data emerging from ongoing clinical trials might change the treatment landscape of ALL and beyond. Early use of blinatumomab in frontline protocols with more advantageous treatment sequences and in combination with other targeted therapies might reduce the failure rates. Exponentially increasing number of novel treatment options and their possible combinations might complicate treatment decision-making without data from randomized trials.

KEYWORDS:

• Acute lymphoblastic leukemia
• bispecific antibodies
• blinatumomab
• cytokine release syndrome
• immunotherapy
• neurotoxicity
• T-cell engagers
• T cells

Article highlights box

• Blinatumomab is a bispecific T-cell engager with dual binding specificities, directing T-cell cytotoxicity towards CD19-expressing target cells, as B-cell precursor acute lymphoblastic leukemia (BCP ALL) cells.

• Its structural features as small size and lack of Fc-domain account for blinatumomab’s somewhat undesirable pharmacokinetic properties (i.e., a short half-life, and requirement for continuous intravenous infusion). At the same time, these factors however result in the formation of strong cytolytic synapses/efficient elimination of target cells and allow a rapid mitigation of the adverse events simply by withdrawal of blinatumomab infusion.

• Blinatumomab has a unique safety profile. Key adverse events include cytokine release syndrome and neurotoxicity, largely both well manageable.

• Blinatumomab efficiently eradicates minimal residual disease and improves the outcomes in BCP ALL patients, at higher rates in patients with low tumor burden and at early stages of disease, compared to heavily pretreated, relapsed and refractory BCP ALL patients. Efforts are made to implement blinatumomab in frontline protocols with optimal treatment combinations/sequences with standard care of chemotherapy.

• Hematopoietic stem cell transplantation (HSCT) prior or following blinatumomab treatment is safe and feasible. In some patients, blinatumomab can also lead to long-term remission without subsequent HSCT.

• Considerable numbers of patients do not respond to blinatumomab or eventually relapse, due to target cell resistance, in cases linked to CD19-target antigen modulation or T-cell dysfunction. Better understanding of response mechanisms is needed to design strategies that further improve the outcome. Combination with checkpoint inhibitors or constructs with other specificities as CD22 or CD20 might reduce the risk of resistance or relapse.

• Novel bispecific antibodies (bsAbs) with new designs improving their potency and pharmacokinetic properties are very effective in in vitro and in pre-clinical studies. In clinics, however, their maximum potency cannot always be reached due to dose-limiting toxicities. Efforts are being made to overcome these hurdles and novel treatment modalities, based on bispecific constructs are in development, and some already in clinic. A wide range of target specificities might potentially bring clinical benefit in multiple hematological and non-hematological malignancies.

Declaration of interest

M Brüggemann is contracted to carry out research for Affimed, Amgen, Regeneron, advisory board of Amgen, Incyte, Speaker bureau of Amgen, Janssen, Pfizer, Roche. CB Baldus is contracted to carry out research for Novartis, advisory board of Amgen. 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 Disclosure

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

Additional information

Funding

The manuscript was funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) – project number 413490537; Deutsche Krebshilfe, project number 70113252; Deutsche José Carreras Leukämie-Stiftung (DJCLS, German Jose Carreras leukemia foundation) project number DJCLS 22R/2019;