Does lineage plasticity enable escape from CAR-T cell therapy? Lessons from MLL-r leukemia

Abstract

The clinical success of engineered, CD19-directed chimeric antigen receptor (CAR) T cells in relapsed, refractory B-cell acute lymphoblastic leukemia (B-ALL) has generated great enthusiasm for the use of CAR T cells in patients with cytogenetics that portend a poor prognosis with conventional cytotoxic therapies. One such group includes infants and children with mixed lineage leukemia (MLL1, KMT2A) rearrangements (MLL-r), who fare much worse than patients with low- or standard-risk B-ALL. Although early clinical trials using CD19 CAR T cells for MLL-r B-ALL produced complete remission in most patients, relapse with CD19-negative disease was a common mechanism of treatment failure. Whereas CD19^neg relapse has been observed across a broad spectrum of B-ALL patients treated with CD19-directed therapy, patients with MLL-r have manifested the emergence of AML, often clonally related to the B-ALL, suggesting that the inherent heterogeneity or lineage plasticity of MLL-r B-ALL may predispose patients to a myeloid relapse. Understanding the factors that enable and drive myeloid relapse may be important to devise strategies to improve durability of remissions. In this review, we summarize clinical observations to date with MLL-r B-ALL and generally discuss lineage plasticity as a mechanism of escape from immunotherapy.

Figure 1.

Clinical and biological differences in CD28- and 4–1BB−containing CAR T cells. Second-generation CARs, consisting of an antigen-binding domain (scFv) connected via an extracellular and transmembrane domain to a co-stimulatory domain (derived from either CD28 or 4–1BB) and the intracellular portion of the CD3z chain. Both CAR formats successfully activate T cells leading to leukemic clearance in preclinical models and in patients; however, each co-stimulatory molecule elicits differences in persistence, T-cell phenotype, and metabolism.

Figure 2.

Waddington landscape depicting the impact of MLL fusion oncoproteins and extrinsic factors on leukemia lineage. (A) The expanded progenitor cell diagram reveals myeloid- or lymphoid-promoting signals (filled arrows) promoting transcription factors (ovals) acting on lineage-directing enhancers (filled rectangles) to maintain exclusive lineage identity. Red double-headed arrows indicate the latent myeloid potential of transformed B-ALL which can overcome the activation energy to lose B-cell characteristics and gain myeloid identity. (B) Lineage switching on CD19-directed therapy (green crescent) as influenced by direct killing of the CD19+ B-ALL and/or impact of the immunotherapy and the niche on lineage decisions within the remaining B-ALL cells.