T-cell redirecting therapies for B-cell non-Hodgkin lymphoma: recent progress and future directions

Abstract

Several key advances in the treatment of B-cell non-Hodgkin lymphoma (B-NHL) over the past two decades have strategically exploited B-cell lineage markers suitable for targeting by immunotherapies. First, the addition of the anti-CD20 monoclonal antibody (mAb) rituximab to a range of standard therapies conferred remarkable outcomes improvements in diverse settings, perhaps most prominently an overall survival advantage in newly diagnosed diffuse large B-cell lymphoma (DLBCL). Subsequently, multiple chimeric antigen receptor (CAR) T-cell therapies targeting CD19 have revolutionized the treatment of relapsed/refractory (rel/ref) DLBCL and are active in other B-NHL subtypes as well. Most recently, the longstanding aspiration to exploit patients’ endogenous T-cells to combat lymphoma has been achieved via T-cell redirecting therapies such as bispecific antibodies (BsAbs) that incorporate dual targeting of a T-cell antigen such as CD3 plus a B-cell antigen such as CD19 or CD20 expressed by the tumor. These novel agents have demonstrated impressive activity as monotherapies in patients with heavily pre-treated, rel/ref B-NHL of a variety of subtypes. Now, myriad clinical trials are exploring combinations of T-cell redirectors with targeted therapies, antibody-drug conjugates, conventional chemotherapy, and even new immunotherapies. Here, we highlight key landmarks in the development of T-cell redirecting therapies for the treatment of B-NHL, emerging evidence and lessons from recent clinical trials, and exciting new directions in this arena.

Sequencing of Anti-CD19 Therapies in the Management of Diffuse Large B-Cell Lymphoma

“…Whatever the reason for looking beyond CAR-T and ASCT, recently approved therapies have broadened the therapeutic armamentarium for these patients to include immunotherapy regimens such as tafasitamab plus lenalidomide, polatuzumab vedotin combined with bendamustine plus rituximab, and loncastuximab tesirine ( 8 ). Bispecific antibody (BsAb) is an emerging therapeutic option for patients with relapsed/refractory (R/R) DLBCL, including the recently approved CD20xCD3-directed antibodies glofitamab and epcoritamab ( 9 , 10 ) and odronextramab, which is currently under regulatory review ( 11 ), with CD19xCD3-targeting bispecifics also in development ( 12 ). However, response data are currently substantially more mature for CD19-based treatments ( 13 – 15 ).…”