New Frontiers in Monoclonal Antibodies for Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Abstract

Diffuse large B-cell lymphoma (DLBCL) is the most common aggressive lymphoma. Approximately 60% of patients are cured with R-CHOP as a frontline treatment, while the remaining patients experience primary refractory or relapsed disease (R/R). The prognosis for R/R DLBCL patients who are neither eligible for autologous stem-cell transplantations nor CAR-T-cell treatment is poor, representing an important unmet need. Monoclonal antibodies (mAbs) have dramatically improved therapeutic options in anti-cancer strategies, offering new opportunities to overcome chemo-refractoriness in this challenging disease, even in cases of primary non-responder DLBCL. Several novel mAbs, characterized by different mechanisms of action and targets, are now available for R/R DLBCL. Unbound mAbs induce an immune response against cancer cells, triggering different mechanisms, including antibody-dependent cellular cytotoxicity (ADCC), activation of antibody-dependent cell-mediated phagocytosis (ADCP) and complement-dependent cytotoxicity (CDC). Antibody-drug conjugates (ADCs) and radioimmunotherapy (RIT), respectively, deliver a cytotoxic payload or a beta-emitter radionuclide to the targeted cells and nearby bystanders. Bispecific T-cell engagers (BiTes) and immune checkpoint inhibitors (ICIs) redirect and enhance the immune response against tumor cells. Here, we review therapeutic strategies based on monoclonal antibodies for R/R DLBCL.

Keywords: antibody-dependent cellular cytotoxicity; bispecific antibodies; diffuse large B-cell lymphoma; immune checkpoint inhibitors; monoclonal antibodies; target therapy.

Figure 1

This figure illustrates the mechanisms of action of therapeutic monoclonal antibodies. The binding of an unbound monoclonal antibody to its antigen induces an immune response against targeted cancer cells through antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated phagocytosis and complement-dependent cytotoxicity. Internalization of antibody–drug conjugates into cancer cells leads to tumor cell death due to the release of cytotoxins. Following apoptosis of the targeted cancer cells and diffusion in the extracellular space, these cytotoxins can promote bystander killing. Similarly, a monoclonal antibody conjugated to a radionuclide delivers radioactive particles to targeted tumor cells as well as nearby tumor cells, resulting in their death. Blocking immune escape mechanisms, such as PD-1/PD-L1 and CD47/SIRPα signaling, restores an appropriate immune response against tumor cells. Bispecific T-cell engagers bind both tumor cells and T cells, redirecting a selective cytotoxic response against cancer cells. ADC: antibody–drug conjugates; TCR: T-cell receptor; MHCI: major histocompatibility complex class I; BiTe: bispecific T-cell engager; RIT: radioimmunotherapy; MAC: membrane attack complex; FcR: Fc receptor.