Promising Immunotherapeutic Modalities for B-Cell Lymphoproliferative Disorders

Abstract

Over the last few years, treatment principles have been changed towards more targeted therapy for many B-cell lymphoma subtypes and in chronic lymphocytic leukemia (CLL). Immunotherapeutic modalities, namely monoclonal antibodies (mAbs), bispecific antibodies (bsAbs), antibody-drug conjugates (ADCs), and chimeric antigen receptor T (CAR-T) cell therapy, commonly use B-cell-associated antigens (CD19, CD20, CD22, and CD79b) as one of their targets. T-cell engagers (TCEs), a subclass of bsAbs, work on a similar mechanism as CAR-T cell therapy without the need of previous T-cell manipulation. Currently, several anti-CD20xCD3 TCEs have demonstrated promising efficacy across different lymphoma subtypes with slightly better outcomes in the indolent subset. Anti-CD19xCD3 TCEs are being developed as well but only blinatumomab has been evaluated in clinical trials yet. The results are not so impressive as those with anti-CD19 CAR-T cell therapy. Antibody-drug conjugates targeting different B-cell antigens (CD30, CD79b, CD19) seem to be effective in combination with mAbs, standard chemoimmunotherapy, or immune checkpoint inhibitors. Further investigation will show whether immunotherapy alone or in combinatory regimens has potential to replace chemotherapeutic agents from the first line treatment.

Treatment of Double-Refractory Chronic Lymphocytic Leukemia—An Unmet Clinical Need

“…It is a CD20 × CD3 IgG1 T-cell engager (TCE). The preliminary results have shown a favorable safety profile and activity even in the high-risk patients (86% had del17p or TP53 mutations, the median number of six previous therapies) [91,112]. In a phase 1b/2 trial, epcoritamab showed clinical activity in patients with high-risk CLL previously treated with two or more lines of systemic therapy, including BTKi (EPCORE CLL-1; NCT04623541).…”

Innovative Combinations, Cellular Therapies and Bispecific Antibodies for Chronic Lymphocytic Leukemia: A Narrative Review

“…Bispecific antibodies (BsAbs) represent a new class of immunotherapeutic drugs; they are engineered to recognize and bind two different antigens [54]. There are two major classes that are categorized based on the presence or the lack of an Fc region.…”

“…Once activated, cytotoxic T lymphocytes release perforins and granzymes, causing the lysis of the target cells. Afterwards, multiple cytokines such as interleukin (IL)-2, IL-6, IL-10, interferon-gamma (IFN-γ) and tumor necrosis factor-alpha are secreted, leading to the activation of other immune cells, such as B cells, macrophages and NK cells [54].…”

Recent Developments in Application of Multiparametric Flow Cytometry in CAR-T Immunotherapy

“…Although some clinical studies have selected markers expressed in subgroups of ALL, such as CD20 [46] and CRLF2 [31] for B-ALL, and TRBC1 and CD1a for T-ALL [47,48]. As to lymphoproliferative disease (LPD), other studies have tried to select lineage markers expressed by mature lymphocytes beside CD19 and CD22 [6, 37], for example, CD20, CD37, and BAFFR for B-LPD, CD5, CD4, TRBC1 for T-LPD, and CD38, BCMA or other markers for multiple myeloma (MM) [9,10,[49][50][51]. Special subtypes of lymphoma have selected corresponding specific antigens as targets, such as CD30 for anaplastic large cell lymphoma (ALCL) and Hodgkin lymphoma (HL) [52][53][54].…”

“…Therefore, we used cCD79a as the main B marker in MRD detection after CD19-CAR-T or CD19/CD22 combined CAR-T treatment, and achieved good clinical evaluation results [3]. Besides the biggest advantage of cCD79a panel is that we can use the same panel for all MRD detection after any B marker CAR-T treatment in the future because it is an intracellular antigen not for CAR-T target [51].…”