Multi Targeted CAR-T Cell Therapies for B-Cell Malignancies

Abstract

Chimeric antigen receptor (CAR) modified T cell therapy has revolutionized the treatment of relapsed and refractory hematological malignancies. Through targeting of the CD19 antigen on B cells durable remissions have been achieved in patients with B cell non-Hodgkin lymphoma and acute lymphoblastic lymphoma. Despite impressive responses, multiple escape mechanisms to evade CAR-T cell therapy have been identified, among which the most common is loss of the target antigen. In this review we will highlight outcomes to date with CD19 CAR-T cell therapy, describe the current limitations of single targeted CAR-T therapies, review identified tumor escape mechanisms, and lastly discuss novel strategies to overcome resistance via multi-targeted CAR-T cells.

Keywords: B-cell ALL; B-cell NHL; CAR-T; antigen escape; immunotherapy.

Figure 1

Mechanisms of CAR-T evasion. (A) Tumor cells, through genetic mutations, can either (i) completely lose CD19 receptor expression or (ii) modify the CD19 receptor such that CAR-T cells can no longer recognize and bind the target. (B) Tumor cells can undergo phenotypic switch to a different lineage that is inherently CD19 negative to evade CAR-T cells. (C) As described in the case report by Ruella et al. (18) lentiviral modification of a single leukemic cell allowed for epitope masking and evasion of CAR-T cell therapy.

Figure 2

Multi-targeted CAR-T approaches. (A) Coadministration—involves production of two separate CAR-T cell products infused together or sequentially. (B) Bicistronic vector—allows expression of 2 different CARs on the same cell. (C) Cotransduction—encode 2 CAR constructs via transduction with multiple vectors. With this process, one will also obtain cells that express each CAR alone. (D) Tandem—encode 2 CARs on same chimeric protein using a single vector.