Abstract
Chimeric antigen receptor (CAR) T-cell therapy has shown promising clinical impact against hematologic malignancies. CD19 is a marker on the surface of normal B cells as well as most B-cell malignancies, and thus has a role as an effective target for CAR T-cell therapy. In numerous clinical data, successes with cell therapy have provided anticancer therapy as a potential therapeutic option for patients who are resistant to standard chemotherapies. However, recent growing evidence showed the limitations of the treatment such as antigen-positive relapse due to poor CAR T-cell persistence and antigen-negative relapses associated with CAR-driven mutations, alternative splicing, epitope masking, low antigen density, and lineage switching. The understanding of the resistance mechanisms to the cell therapy has developed novel potential treatment strategies, including dual-targeting therapy (dual and tandem CAR), and armored and universal CAR T-cell therapies. In this review, we provide an overview of resistance mechanisms to CD19 CAR T-cell therapy in B-cell malignancies and also review therapeutic strategies to overcome these resistances.
Highlights
Chimeric antigen receptor (CAR) is a synthetic tumor-specific receptor that can bind to target cell surface antigens via a single-chain variable fragment recognition domain, hinge regions, a transmembrane domain, and an intracellular signaling domain transmitting activation signals [1,2,3]
The results demonstrated favorable results by targeting CD19, CD20, or CD30, and the most promising outcomes have been achieved in CD19-specific CAR T-cells for B-cell acute lymphoblastic leukemia (B-ALL) with a high complete remission (CR) rate of 70–94% [10,11,12,13,14,15]
Poor CAR T-cell persistence or transient B-cell aplasia indicates an inconsistent effect of immunotherapy, which is often associated with an early relapse of leukemic or lymphoma cells within a few months after induction of successful remission
Summary
Chimeric antigen receptor (CAR) is a synthetic tumor-specific receptor that can bind to target cell surface antigens via a single-chain variable fragment (scFv) recognition domain, hinge regions, a transmembrane domain, and an intracellular signaling domain transmitting activation signals [1,2,3]. Acting as a B-cell co-receptor, CD19 supports early B-cell development and mediates the maturation of peripheral blood B cells [20,21] It is a prospective antigen for CAR T-cell therapy. Some clinical data of the cell therapy of relapsed or refractory CD19-positive B-cell malignancies demonstrated excellent long-term remission, and patients receiving the treatment were potentially cured [10,11,12,13,14,15,16,17,18,19]. Active CAR T-cell-mediated immune surveillance plays an important role in durable remission after the cell therapy [10]. We will review the various mechanisms of resistance to the therapy in B-cell hematologic malignancies
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