Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma

SIMPLE SUMMARY: The activity of novel therapies that utilize patient’s own T-cells to induce remission of B-cell non-Hodgkin lymphoma (B-NHL), including chronic lymphocytic leukemia (CLL), is still suboptimal. In this review, we summarize the clinical efficacy of T-cell-based therapies in B-NHL and provide a biologic rationale for the observed (lack of) responses. We describe and compare the acquired T-cell dysfunctions that occur in the different subtypes of B-NHL. Furthermore, we discuss new insights that could enhance the efficacy of T-cell-based therapies for B-NHL and CLL. ABSTRACT: The next frontier towards a cure for B-cell non-Hodgkin lymphomas (B-NHL) is autologous cellular immunotherapy such as immune checkpoint blockade (ICB), bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T-cells. While highly successful in various solid malignancies and in aggressive B-cell leukemia, this clinical success is often not matched in B-NHL. T-cell subset skewing, exhaustion, expansion of regulatory T-cell subsets, or other yet to be defined mechanisms may underlie the lack of efficacy of these treatment modalities. In this review, a systematic overview of results from clinical trials is given and is accompanied by reported data on T-cell dysfunction. From these results, we distill the underlying pathways that might be responsible for the observed differences in clinical responses towards autologous T-cell-based cellular immunotherapy modalities between diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). By integration of the clinical and biological findings, we postulate strategies that might enhance the efficacy of autologous-based cellular immunotherapy for the treatment of B-NHL.