T-cell exhaustion in multiple myeloma

ABSTRACT

Introduction

Chimeric Antigen Receptor (CAR) T-cells and Bispecific Antibodies (BsAb) are the leading platforms for redirecting the immune system against cells expressing the specific antigen, revolutionizing the treatment of hematological malignancies, including multiple myeloma (MM). In MM, drug-resistant relapses are the main therapy-limiting factor and the leading cause of why the disease is still considered incurable. T-cell-engaging therapies hold promise in improving the treatment of MM. However, the effectiveness of these treatments may be hindered by T-cell fitness. T-cell exhaustion is a condition of a gradual decline in effector function, reduced cytokine secretion, and increased expression of inhibitory receptors due to chronic antigen stimulation.

Areas covered

This review examines findings about T-cell exhaustion in MM in the context of T-cell redirecting BsAbs and CAR-T treatment.

Expert opinion

The fitness of T-cells has become an important factor in the development of T-cell redirecting therapies. The way T-cell exhaustion relates to these therapies could affect the further development of CAR and BsAbs technologies, as well as the strategies used for clinical use. Therefore, this review aims to explore the current understanding of T-cell exhaustion in MM and its relationship to these therapies.

KEYWORDS:

• Multiple myeloma
• chimeric antigen receptor
• CAR-T
• BsAbs
• T-cell exhaustion
• T-lymphocytes
• hematologic neoplasms
• bispecific antibodies

Article highlights

• T-cell exhaustion is a progressive decline in effector function, reduced cytokine secretion, and increased expression of inhibitory receptors due to chronic antigen stimulation.

• From early stages, multiple myeloma is associated with compromised T-cell function, and disease progression and relapses are accompanied by deepening T-cell exhaustion.

• Studies have demonstrated the remarkable efficacy of T-cell redirecting therapies in the treatment of refractory and relapsed multiple myeloma.

• Pre-existing T-cell exhaustion can lead to suboptimal efficacy of T-cell redirecting therapies in multiple myeloma.

• Chimeric Antigen Receptors and Bispecific T-cell Engaging constructs promote T-cell exhaustion, thereby self-limiting the efficacy.

• Alternate dosing, use in earlier lines of treatment, combination with different drug classes, and next-generation constructs could be strategies for ameliorating the T-cell exhaustion effect.

Declaration of interest

The authors have no 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. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

One reviewer has acted in a consulting or advisory role for SparkCures, Sanofi Pasteur, Genentech/Roche, Janssen Oncology, Bristol-Myers Squibb/Celgene, Caribou Biosciences, Pfizer, Karyopharm Therapeutics, Legend Biotech, Adaptive Biotechnologies, and GSK, and has also received research funding from Novartis, with funding from Pack Health going to to their institution. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.