Single-Agent and Associated Therapies with Monoclonal Antibodies: What About Follicular Lymphoma?
by
,
Gabriella Cancemi
1, 
Chiara Campo
1,
Santino Caserta
2,
Iolanda Rizzotti
1 and
Donato Mannina
1,* 1
Hematology Unit, Oncology-Hematology Department, Azienda Ospedaliera Papardo, 98158 Messina, Italy
2
Hematology Unit, Department of Human Pathology in Adulthood and Childhood “Gaetano Barresi”, University of Messina, Via Consolare Valeria, 98125 Messina, Italy
*
Author to whom correspondence should be addressed.
Cancers 2025, 17(10), 1602; https://doi.org/10.3390/cancers17101602
Submission received: 31 March 2025
/
Revised: 1 May 2025
/
Accepted: 7 May 2025
/
Published: 8 May 2025
(This article belongs to the Special Issue Monoclonal Antibodies in Lymphoma)
Simple Summary
Monoclonal antibodies are crucial in treating follicular lymphoma, offering targeted therapy with reduced toxicity. Anti-CD20 monoclonal antibodies like rituximab and obinutuzumab have improved survival rates, making immunochemotherapy the standard. However, resistance due to CD20 downregulation or immune escape has led to next-generation drugs, such as bispecific antibodies and antibody–drug conjugates. These innovations, combined with immune checkpoint inhibitors, enhance outcomes. Despite progress, several challenges persist, including the optimal sequence of chemoimmunotherapy, bispecific antibodies, and CAR-T cell therapy; the management of immune-related toxicities, cytokine release syndrome and neurotoxicity; and the identification of predictive biomarkers, such as EZH2 mutations, minimal residual disease (MRD) status, and MHC class II expression, to better personalize treatment approaches.
Abstract
Monoclonal antibodies (mAbs) have become a cornerstone in the treatment of follicular lymphoma (FL), offering highly specific therapeutic targeting that enhances efficacy while minimizing systemic toxicity. Their mechanisms of action include antibody-dependent cellular cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct apoptotic signaling, effectively mediating malignant B-cell depletion. Anti-CD20 mAbs, such as rituximab and obinutuzumab, have significantly improved progression-free survival (PFS) and overall survival (OS), establishing immunochemotherapy as the standard of care for FL. However, the emergence of treatment resistance, often characterized by CD20 antigen downregulation or immune escape, has prompted the development of next-generation mAbs with enhanced effector functions. Bispecific antibodies (BsAbs), which simultaneously engage CD20-expressing tumor cells and CD3-positive cytotoxic T cells, have emerged as a novel immunotherapeutic strategy, redirecting T-cell activity to eliminate malignant B cells independently of major histocompatibility complex (MHC) antigen presentation. Additionally, antibody–drug conjugates (ADCs) offer a targeted cytotoxic approach by delivering potent chemotherapeutic payloads directly to tumor cells while limiting off-target effects. The integration of mAbs with immune checkpoint inhibitors and immunomodulatory agents is further enhancing treatment outcomes by overcoming immunosuppressive mechanisms within the tumor microenvironment. Despite these advancements, challenges remain, including optimizing the treatment sequence, mitigating immune-related toxicities—particularly cytokine release syndrome (CRS)—and identifying predictive biomarkers to guide patient selection. As the role of monoclonal antibodies continues to expand, their integration into therapeutic regimens is transforming the management of FL, paving the way for chemotherapy-free treatment approaches and long-term disease control. This review provides an updated overview of mAbs therapies for FL, emphasizing the advances brought by BsAbs and ADCs toward more tailored and effective treatments.
