The future of CAR T-cell therapy for B-cell acute lymphoblastic leukemia in pediatrics and adolescents

ABSTRACT

Introduction

Antigen downregulation and early chimeric antigen receptor (CAR) T-cell loss have emerged as two major challenges threatening outcomes following CD19-specific CAR T-cell therapy for children and young adults with B-cell acute lymphoblastic leukemia (B-ALL). In addressing the future of CAR T-cell therapy for B-ALL, innovative strategies to avert antigen downregulation and enhance CAR persistence warrant prioritized focus.

Areas covered

We describe promising engineering strategies to refine CAR constructs to reverse exhaustion, develop regulatable CARs, optimize manufacturing, enrich for immune memory, and disrupt immune inhibition. We additionally focus on alternative targeting to CD19-monospecific targeting and contextualize possibilities for expanded CAR utilization.

Expert opinion

We describe research advances as they are independently reported, however, anticipate an integrative strategy incorporating complementary modifications will be required to effectively address CAR loss, overcome antigen downregulation, and enhance reliability and durability of CAR T-cell responses for B-ALL.

KEYWORDS:

• Chimeric antigen receptor (CAR)
• CAR T cell Therapy
• immunotherapy
• acute lymphoblastic leukemia (ALL)
• pediatric oncology

Article highlights

• Early CAR loss and antigen downregulation are tow major challenges threatening durability of remissions following CD19-CAR T-cell therapy

• Next generation strategies to enhance post-CAR outcomes should focus on enhancing CAR persistence and avoiding antigen downregulation

• Strategies to reverse CAR T-cell exhaustion and loss include generating titratable CARs, engineering CAR modifications optimized for persistence, shortening the manufacturing window, enriching CAR T cells for memory subsets and disrupting immune-mediated rejection

• Strategies to address antigen downregulation include antigen discovery efforts beyond CD19, development of multi-specific CAR platforms, clarifying optimal approach toward equipotent multi-specificity and engineering maneuvers to decrease CAR activation threshold.

• It is crucial to establish prognosticators of antigen downregulation and early CAR loss, so high risk patients can be identified a priori and managed accordingly.

Declaration of Interest

CL Mackall is an inventor on several patents related to CAR T cell therapies. CL Mackall is a cofounder of Lyell Immunopharma, CARGO Therapeutics and Link Cell Therapies, which are developing CAR-based therapies, and consults for Lyell, Syncopation, Link, Apricity, Nektar, Immatics, Ensoma, Mammoth, Glaxo Smith Kline and Bristol Myers Squibb. L Schultz served as an advisor on an advisory board for Novartis. 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 or other relationships to disclose.

Additional information

Funding

This paper was not funded.