Conclusions Primary refractory/relapsed DLBCL remains a challenging disease, particularly in those patients who are not eligible for ASCT/CAR-T-cell therapy, failed these treatments or experienced more than one relapse

Conclusions Primary refractory/relapsed DLBCL remains a challenging disease, particularly in those patients who are not eligible for ASCT/CAR-T-cell therapy, failed these treatments or experienced more than one relapse. The landscape of anti-DLBCL treatment is evolving, and only recently, the replacement of vincristine with polatuzumab vedotin in the R-CHOPthe pola-R-CHP regimenhas demonstrated higher results as a frontline treatment [18]. 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). AntibodyCdrug 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: diffuse large B-cell lymphoma, monoclonal antibodies, target therapy, bispecific antibodies, antibody-dependent cellular cytotoxicity, immune checkpoint inhibitors 1. Introduction Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma and the most common subtype of non-Hodgkins lymphoma (NHL), accounting for approximately 30C40% of all diagnoses of NHL. The prevalence is higher in low/middle-income countries (~42.5%) than in high-income countries (~28.9%), with a median age WP1130 (Degrasyn) at diagnosis of 53 and 65 years, respectively [1,2,3]. Most diagnoses are found in previously healthy patients, without any history of hematological malignancies, though a fraction of cases may arise from the transformation of a previous low-grade B-cell lymphoma. The introduction of the anti-CD20 monoclonal antibody (mAb) rituximab in the CHOP regimen (R-CHOP) significantly improved the cure rate to 60% [4,5]. No other regimen, including intensified chemoimmunotherapy [6,7,8], use of second-generation anti-CD20 mAb [9], maintenance therapy [10,11,12] or targeted drugs [13,14,15,16,17], proved to be superior to R-CHOP in CALNB1 terms of overall survival (OS) and progression-free survival (PFS). Recently, pola-R-CHP, in which vincristine was replaced with the anti-CD79b mAb polatuzumab vedotin, has been proven to lower the risk of disease progression in previously untreated DLBCL [18]. Forty percent of patients have a refractory or relapsed disease (R/R DLBCL). Primary refractory disease (10C15% of cases) is defined as a lack of response to treatment, whereas relapsed disease (20C30% of cases), which usually occurs within the first 2 years from the end of treatment, is defined by the appearance of new lesions after achieving a complete response [19,20]. The prognosis for R/R DLBCL is very poor, particularly for primary refractory disease or early WP1130 (Degrasyn) relapse (relapse within 3 to 6 months), in WP1130 (Degrasyn) which the median OS is approximately 6 months [21]. The salvage regimen in transplantable-eligible patients relies on a rituximab-based chemoimmunotherapy WP1130 (Degrasyn) followed by autologous stem-cell transplantation (ASCT). However, only 60% of these patients obtain a sustained remission with a 4-year progression-free survival (PFS) and OS, respectively, of 56% and 65% and an event-free survival (EFS) of 30% [22]. Most R/R DLBCL patients, however, are not ASCT eligible due to age, comorbidities or an inadequate response to salvage chemoimmunotherapy. During the last few years, the advent of new treatments has provided alternatives to conventional therapies, in many cases obtaining sustained remission and survival improvements. The aim of this review is to provide a focus on novel mAbs in the setting of R/R DLBCL (Figure 1). Open in a separate window 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 antibodyCdrug conjugates into cancer cells WP1130 (Degrasyn) 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.