Abstract
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.
Highlights
The most common first-line treatment for diffuse large B-cell lymphoma (DLBCL) is chemoimmunotherapy containing rituximab, the so-called R-CHOP regimen, which fails in 30–40% of patients
It has been demonstrated that natural killer (NK) cells are the major effectors of antibody-dependent cellular cytotoxicity (ADCC) [21]
74 Non-Hodgkin lymphoma (NHL) patients demonstrated that low killer cell Ig–like receptors (KIRs) ligand number and high frequency of KIRpositive NK cells, which are notably efficient in driving RTX-mediated ADCC, correlated with improved complete response (CR) and prognosis
Summary
Non-Hodgkin lymphoma (NHL) is the most frequent hematological neoplasm in the world [1] with more than 544,000 new NHL cases diagnosed in 2020 (2.8% of all cancer diagnoses) [2]. Of all the NHL subtypes, the most common is diffuse large B-cell lymphoma (DLBCL), accounting for approximately 40% of lymphoma cases. The most common first-line treatment for DLBCL is chemoimmunotherapy containing rituximab, the so-called R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine), which fails in 30–40% of patients. R/r patients have gained the access to adoptive therapy using genetically engineered T cells with chimeric antigen receptor (CAR-T cells) targeting DLBCL-expressed surface antigens. Promising results of this treatment strategy have been observed in the case of CD19-CARs. Three of them, i.e., axicabtagene ciloleucel (Yescarta, Kite), lisocabtagene maraleucel (Breyanzi, Bristol Myers Squibb), and tisagenlecleucel (Kymriah, Novartis) are licensed to treat DLBCL patients [7]. Years of employment of rituximab as a core of first-line treatment and recent observations on CAR-T cell therapy clearly demonstrate that the use of immunotherapy invariably leads to the induction of resistance [8]. This review aims at summarizing the mechanisms of resistance induced by various forms of immunotherapy used in DLBCL (Figure 1)
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