Bispecific CAR T-cells for B-cell Malignancies

ABSTRACT

Introduction

Chimeric antigen receptor (CAR)-modified T-cell therapy has revolutionized the treatment of relapsed/refractory B-cell malignancies including acute lymphoblastic leukemia and non-Hodgkin lymphoma. All of the CARs approved for clinical use in treating B-cell malignancies are directed against a single antigen, CD19. Although the initial response rates are high, a significant number of patients relapse, with antigen loss being one proposed mechanism of treatment failure. Multi-targeted CAR T approaches are now being developed to overcome this limitation of currently approved CAR products.

Areas covered

Here, we discuss the mechanism of antigen loss, various bispecific CAR T-cell constructs, and their efficacy and safety in the preclinical as well as clinical settings.

Expert opinion

Although CD19 CAR T-cells have significantly improved response rates in relapsed/refractory B-cell malignancies, relapse remains a major barrier to long-term survival. Bispecific CAR T-cells offer an alternative approach to mitigate relapse associated with antigen loss. In B-cell malignancies, various bispecific CAR constructs are being studied. The CD19/CD20 and CD19/CD22 bispecific CARs have shown a favorable efficacy and safety profile in phase I trials. However, larger phase II studies and longer follow-ups are needed to better assess their efficacy and safety in patients with relapsed/refractory B-cell malignancies.

KEYWORDS:

• CAR T-cell therapy
• Non-Hodgkin lymphoma
• acute lymphoblastic leukemia
• antigen loss
• bispecific CARs
• bicistronic CARs

Article highlights

• Loss of antigen is an important mechanism of resistance leading to relapse after monospecific CAR T-cells, leading to a significant rate of relapse.

• Targeting multiple agents may provide a benefit in preventing relapse due to antigen loss and treating CD19^– relapse by simultaneously targeting two antigens expressed by B-cells.

• There are various methods of targeting multiple antigens through CAR T-cells, including coadministration of CARs targeting different antigens, cotransduction, bicistronic CARs, and tandem CARs.

• CD19/CD20 and CD19/CD22 combinatorial CAR products have demonstrated favorable safety and efficacy against B-cell malignancies in preclinical studies and in early phase 1 clinical trials.

• Various other antigens on B-cells are being investigated to increase the anti-tumor activity and mitigate the side effects of on-target off-tumor effects.

• Studies are ongoing to target multiple antigens (trispecific and combinatorial CARs) to enhance the efficacy of CAR T-cells.

Disclosure statement

N Shah reports participation on advisory boards and/or consultancy for Kite Pharma, TG Therapeutics, Miltenyi Biotec, Eli Lilly, Epizyme, Legend, Incyte, Novartis, and Umoja, as well as the receipt of research funding and honoraria from Miltenyi Biotec. 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

A reviewer on this manuscript has disclosed that they are an investigator of bispecific CAR for Miltenyi and Novartis. Another reviewer on this manuscript has disclosed that they have received research funding to their institution from Regeneron, AbbVie, Genentech, Roche, and Pharmacyclics. Their spouse is an employee of Sanofi. Peer reviewers on this manuscript have no other relevant financial relationships or otherwise to disclose.

Additional information

Funding

This paper was not funded.