MECHANISMS OF RESISTANCE TO T-CELL REDIRECTING THERAPIES

Abstract

T-cell redirecting therapies, have revolutionized the management of diverse malignancies, especially B-cell non-Hodgkin lymphomas. Currently approved such therapies include T-cells that are engineered to express chimeric antigen receptors (CAR-T cells) and bispecific antibodies that bridge T-cells to diverse tumor antigens. Yet despite their remarkable efficacy and curative potential, resistance and relapse to these therapies remain significant hurdles, and unfortunately, still observed in most patients today. This presentation will explore the tumor-intrinsic mechanisms that contribute to such resistance in mature B-cell neoplasms, while also considering the roles of T-cell dysfunction and the tumor microenvironment (TME) in resistance phenotypes.

I will review data from several studies that have highlighted key mechanisms and pathways underlying such tumor intrinsic resistance. In one key study by Sworder et al. (Cancer Cell, 2023) a comprehensive simultaneous tumor and effector profiling (STEP) approach has been described to investigate resistance determinants in large B-cell lymphomas treated with anti-CD19 CAR T-cells. In addition to genetic and epigenetic mechanisms known to hamper target antigen expression of key tumor markers (such as CD19, CD20, CD22, and BCMA), these studies have revealed that genetic alterations in B cell identity genes like PAX5 and IRF8 may lead to lineage switch or loss of target antigens. Separately, these studies show how somatic gains driving upregulation of key immune checkpoints like PD-L1 upregulation can help tumors evade T-cell attacks. For bispecific antibodies, similar mechanisms, such as antigen loss, are also observed, suggesting shared challenges across therapies.

When considering non-tumor intrinsic mechanisms of resistance, the TME is also known to play a crucial role, with research indicating that immune-suppressed TME profiles correlate with poorer outcomes, likely by hindering T-cell function through axes such as PD-1, TIM-3, suppressive actions of Tregs, MDSCs, inhibitory cytokines, and others. T-cell exhaustion, driven by chronic antigen exposure and TME immunosuppression, is known to reduce effector functions and persistence, impacting both CAR-T and bispecific antibody efficacy. Conversely, TMEs with high B cell proliferation may predict better CAR-T responses, an unexpected feature that could also guide therapy selection.

I will highlight how such approaches to integrative genomic profiling, TME analysis, and T-cell functional assessments can enhance outcome prediction and personalize T-cell therapies. In addition to defining key gaps in our current knowledge, I will describe strategies to help bridge these gaps, toward optimizing existing therapies and developing next-generation interventions to overcome resistance, potentially improving long-term outcomes for patients with lymphomas and other tumors.

Keywords: aggressive B-cell non-Hodgkin lymphoma

No potential sources of conflict of interest.