Molecular Aspects of Resistance to Immunotherapies-Advances in Understanding and Management of Diffuse Large B-Cell Lymphoma.

Despite the unquestionable success achieved by rituximab-based regimens in the management of diffuse large B-cell lymphoma (DLBCL), the high incidence of relapsed/refractory disease still remains a challenge. The widespread clinical use of chemo-immunotherapy demonstrated that it invariably leads to the induction of resistance; however, the molecular mechanisms underlying this phenomenon remain unclear. Rituximab-mediated therapeutic effect primarily relies on complement-dependent cytotoxicity and antibody-dependent cell cytotoxicity, and their outcome is often compromised following the development of resistance. Factors involved include inherent genetic characteristics and rituximab-induced changes in effectors cells, the role of ligand/receptor interactions between target and effector cells, and the tumor microenvironment. This review focuses on summarizing the emerging advances in the understanding of the molecular basis responsible for the resistance induced by various forms of immunotherapy used in DLBCL. We outline available models of resistance and delineate solutions that may improve the efficacy of standard therapeutic protocols, which might be essential for the rational design of novel therapeutic regimens.

CD37 in B Cell Derived Tumors-More than Just a Docking Point for Monoclonal Antibodies.

CD37 is a tetraspanin expressed prominently on the surface of B cells. It is an attractive molecular target exploited in the immunotherapy of B cell-derived lymphomas and leukemia. Currently, several monoclonal antibodies targeting CD37 as well as chimeric antigen receptor-based immunotherapies are being developed and investigated in clinical trials. Given the unique role of CD37 in the biology of B cells, it seems that CD37 constitutes more than a docking point for monoclonal antibodies, and targeting this molecule may provide additional benefit to relapsed or refractory patients. In this review, we aimed to provide an extensive overview of the function of CD37 in B cell malignancies, providing a comprehensive view of recent therapeutic advances targeting CD37 and delineating future perspectives.

CD20 expression regulates CD37 levels in B-cell lymphoma - implications for immunotherapies.

Rituximab (RTX) plus chemotherapy (R-CHOP) applied as a first-line therapy for lymphoma leads to a relapse in approximately 40% of the patients. Therefore, novel approaches to treat aggressive lymphomas are being intensively investigated. Several RTX-resistant (RR) cell lines have been established as surrogate models to study resistance to R-CHOP. Our study reveals that RR cells are characterized by a major downregulation of CD37, a molecule currently explored as a target for immunotherapy. Using CD20 knockout (KO) cell lines, we demonstrate that CD20 and CD37 form a complex, and hypothesize that the presence of CD20 stabilizes CD37 in the cell membrane. Consequently, we observe a diminished cytotoxicity of anti-CD37 monoclonal antibody (mAb) in complement-dependent cytotoxicity in both RR and CD20 KO cells that can be partially restored upon lysosome inhibition. On the other hand, the internalization rate of anti-CD37 mAb in CD20 KO cells is increased when compared to controls, suggesting unhampered efficacy of antibody drug conjugates (ADCs). Importantly, even a major downregulation in CD37 levels does not hamper the efficacy of CD37-directed chimeric antigen receptor (CAR) T cells. In summary, we present here a novel mechanism of CD37 regulation with further implications for the use of anti-CD37 immunotherapies.

In Vitro Diffuse Large B-Cell Lymphoma Cell Line Models as Tools to Investigate Novel Immunotherapeutic Strategies.

Despite the high incidence of diffuse large B-cell lymphoma (DLBCL), its management constitutes an ongoing challenge. The most common DLBCL variants include activated B-cell (ABC) and germinal center B-cell-like (GCB) subtypes including DLBCL with MYC and BCL2/BCL6 rearrangements which vary among each other with sensitivity to standard rituximab (RTX)-based chemoimmunotherapy regimens and lead to distinct clinical outcomes. However, as first line therapies lead to resistance/relapse (r/r) in about half of treated patients, there is an unmet clinical need to identify novel therapeutic strategies tailored for these patients. In particular, immunotherapy constitutes an attractive option largely explored in preclinical and clinical studies. Patient-derived cell lines that model primary tumor are indispensable tools that facilitate preclinical research. The current review provides an overview of available DLBCL cell line models and their utility in designing novel immunotherapeutic strategies.

The "Magic Bullet" Is Here? Cell-Based Immunotherapies for Hematological Malignancies in the Twilight of the Chemotherapy Era.

Despite the introduction of a plethora of different anti-neoplastic approaches including standard chemotherapy, molecularly targeted small-molecule inhibitors, monoclonal antibodies, and finally hematopoietic stem cell transplantation (HSCT), there is still a need for novel therapeutic options with the potential to cure hematological malignancies. Although nowadays HSCT already offers a curative effect, its implementation is largely limited by the age and frailty of the patient. Moreover, its efficacy in combating the malignancy with graft-versus-tumor effect frequently coexists with undesirable graft-versus-host disease (GvHD). Therefore, it seems that cell-based adoptive immunotherapies may constitute optimal strategies to be successfully incorporated into the standard therapeutic protocols. Thus, modern cell-based immunotherapy may finally represent the long-awaited "magic bullet" against cancer. However, enhancing the safety and efficacy of this treatment regimen still presents many challenges. In this review, we summarize the up-to-date state of the art concerning the use of CAR-T cells and NK-cell-based immunotherapies in hemato-oncology, identify possible obstacles, and delineate further perspectives.