The Role of the Tumor Microenvironment in T-Cell Redirecting Therapies of Large B-Cell Lymphoma: Lessons Learned from CAR-T to Bispecific Antibodies
RM Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantation, Pavlov University, 191144 St. Petersburg, Russia
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Author to whom correspondence should be addressed.
Cancers 2025, 17(2), 317; https://doi.org/10.3390/cancers17020317
Submission received: 12 September 2024
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Revised: 8 January 2025
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Accepted: 14 January 2025
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Published: 20 January 2025
(This article belongs to the Special Issue CAR T Cells in Lymphoma and Multiple Myeloma)
Simple Summary
Large B-cell lymphoma (LBCL) is a type of blood cancer that can be challenging to treat, especially when it does not respond to standard chemotherapy or relapses after treatment. New therapies, such as CAR-T cells and bispecific antibodies, have shown promise in treating these cases. However, not all patients benefit equally from these treatments, highlighting the need for new ways to predict treatment response. This study focuses on the tumor microenvironment, which includes the immune cells and molecules surrounding the LBCL tumor cells. By understanding how this environment affects CAR-T and bispecific antibody treatment outcomes, this manuscript aims to identify factors that can help predict success or resistance to therapy. These insights could lead to more personalized treatment approaches and improved outcomes for patients with LBCL.
Abstract
T-cell redirecting therapies, which include chimeric antigen receptor T-cells (CAR-Ts) and bispecific antibodies (BSAs), have revolutionized the treatment of relapsed\refractory large B-cell lymphoma (LBCL). Expanding clinical experience with these advanced therapies shows the potential for the optimization of their use with combination or consolidation strategies, which necessitates the prognostic stratification of patients. While traditional clinical prognostic factors identified in the era of chemotherapy are characterized by limited value, the tumor microenvironment (TME) is becoming a new prognostic cluster. We examine how the heterogeneity of LBCL, characterized by variations in tumor parameters and differences in TME immune cell composition, immune checkpoint expression, and cytokine milieu, correlates with both positive responses and resistance to treatment. While classical parameters such as histological subtype, cell of origin, and target antigen expression lack proven prognostic value for T-cell redirecting therapies, the density and functional state of tumor-infiltrating lymphocytes, tumor-associated macrophages, and immune checkpoint molecules are shown to be critical determinants of therapeutic success, particularly in CAR-T therapy. We identify several gaps in the current knowledge and suggest that the insights gained from CAR-T experience could be instrumental in refining BSA applications. This report also highlights limitations in the current knowledge, as TME data derive from a limited number of registrational trials with varying methodologies, complicating cross-study comparisons and often focusing on immediate response metrics rather than long-term outcomes. By dissecting the complex interactions within the TME, this review aims to identify new prognostic factors and targets, ultimately fostering more effective and tailored treatment strategies for LBCL patients.
