Mechanisms of immune evasion and novel treatments for relapsed and refractory diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease characterized by varying biological mechanisms, clinical manifestations, and responses to treatment. This malignancy arises due to multiple mechanisms, including genetic remodeling, inhibition of differentiation, escape from immune surveillance, and alterations in signal transduction pathways. These complexities have significant implications for the prognostication and clinical management of DLBCL. In this review, we delve into the mechanisms of immune evasion employed by DLBCL and discuss the latest immunotherapy treatment strategies for relapsed and refractory DLBCL.

Epigenetic and Genetic Alterations in DLBCL

Over 70% of DLBCL cases harbor genetic alterations that impact immune status. These alterations often lead to impaired immune recognition of tumor cells. One example is the downregulation of major histocompatibility complex (MHC) class I and II molecules, crucial for antigen presentation to T-cells. This reduction in MHC expression enables tumor cells to evade immune surveillance.

Furthermore, specific genetic rearrangements, such as the t(14;18) translocation juxtaposing the BCL-2 oncogene and enhancer of heavy chain immunoglobulin, lead to overexpression of BCL-2. This, in combination with MYC rearrangements, results in a poor prognosis and is categorized as double-hit lymphoma (DHL). Conversely, isolated BCL-2 rearrangements without MYC rearrangement may not always portend a worse prognosis but can be associated with the double-expressor lymphoma (DEL) phenotype.

Mechanisms of Immune Evasion

DLBCL utilizes several mechanisms to evade the immune system. One mechanism involves downregulation of T-cell costimulatory molecules like CD80 and CD86, impairing the ability of antigen-presenting cells to stimulate T-cell activation. Additionally, DLBCL cells express immunomodulatory molecules such as programmed death-ligand 1 (PD-L1) and CD55, which interfere with T-cell effector functions and promote immune evasion.

The loss of expression of certain molecules like MHC-I and MHC-II also plays a critical role in immune evasion. The absence of these molecules disrupts the formation of the immunological synapse between CD8+ T-cells and antigen-presenting cells, hindering T-cell-mediated immune responses against tumor cells.

Novel Treatments for Relapsed and Refractory DLBCL

Immunotherapy with Monoclonal Antibodies

Rituximab, a monoclonal antibody targeting CD20, has revolutionized the treatment of DLBCL. By inducing direct cytotoxicity, inhibiting proliferation, and promoting antibody-dependent cellular cytotoxicity (ADCC), rituximab enhances immune-mediated tumor eradication. Its integration into chemotherapy regimens has significantly improved patient outcomes.

Chimeric Antigen Receptor T-cell (CAR-T) Therapy

CAR-T-cell therapy is an emerging and promising treatment for relapsed and refractory DLBCL. This approach involves genetically engineering T-cells to express CARs that target specific tumor antigens, such as CD19 or CD20. These CAR-T cells demonstrate high complete response rates but are limited by factors such as T-cell exhaustion and CAR-T-cell resistance. Current trials are underway to optimize CAR-T-cell design and efficacy.

Bispecific Antibodies

Bispecific antibodies (BsAbs) offer another novel therapeutic option. These antibodies are designed to bind to two different antigens simultaneously, enhancing their effector functions. Examples include tafasitamab and regen-cov, which have demonstrated promising efficacy in clinical trials for relapsed or refractory DLBCL.

Checkpoint Inhibitors

Inhibitors of checkpoint molecules like PD-1 and CTLA-4 are being investigated in combination with CAR-T-cell therapy and other immunotherapies to overcome T-cell exhaustion and improve responses.

Conclusions

The complex interplay between immune dysregulation and the underlying pathophysiology of DLBCL necessitates the development of innovative immunotherapies. Recent advances in the understanding of immune evasion mechanisms have paved the way for the development of novel therapeutic strategies, including monoclonal antibodies, CAR-T-cell therapy, bispecific antibodies, and checkpoint inhibitors. These treatments offer the potential for improved clinical outcomes and survival rates for patients with relapsed and refractory DLBCL.

Full text

https://www.xiahepublishing.com/2996-3427/OnA-2024-00006

The study was recently published in the Oncology Advances.

Oncology Advances is dedicated to improving the diagnosis and treatment of human malignancies, advancing the understanding of molecular mechanisms underlying oncogenesis, and promoting translation from bench to bedside of oncological sciences. The aim of Oncology Advances is to publish peer-reviewed, high-quality articles in all aspects of translational and clinical studies on human cancers, as well as cutting-edge preclinical and clinical research of novel cancer therapies.

Follow us on X: @xiahepublishing

Follow us on LinkedIn: Xia & He Publishing Inc.