Emerging immunotherapy advances for non-Hodgkin lymphomas: engaging T cells in the fight

The treatment landscape of B-cell non-Hodgkin lymphoma (B-NHL) has been rapidly transformed by the emergence of T-cell engaging (TCE) therapies. Within the past decade, anti-CD19 chimeric antigen receptor (CAR) T-cell therapies have moved from relapsed/refractory to second-line settings in aggressive large B-cell lymphomas and are now also approved for R/R follicular lymphoma, mantle cell lymphoma, and chronic lymphocytic leukemia. More recently, bispecific antibodies with dual engagement of CD20 × CD3 have emerged as an alternative TCE option with regulatory approval as monotherapies in several relapsed/refractory B-cell lymphomas. Common investigational themes for TCE therapies include earlier integration in the treatment paradigm, testing combination approaches, and considering optimal sequencing approaches. Despite major progress, there remains opportunity for technical innovations that may improve efficacy, attenuate toxicity, and ease the sometimes complex logistics around treatment delivery. Alternative and multiantigen targets are being explored in CAR T-cell constructs as well as bispecific antibodies, with some of these approaches now in early-phase clinical trials. Strategies to improve CAR T manufacturing, optimize T-cell fitness, and design novel "armored" CAR T-cells designs are actively being tested in preclinical and early-phase clinical data. From a safety perspective, much progress has been made in reducing the burden of side effects and broadening access; however, barriers remain before TCE therapies can be widely available to all patients. This brief review addresses some of the latest strategies being tested to elevate TCE therapies as pillars of immunotherapy for B-NHL.