Yan Leyfman, Medical Oncologist, Co-Founder and Executive Director of MedNews Week, shared a post on LinkedIn:
“Targeting tumor-associated macrophages to overcome CAR T-cell resistance in DLBCL
CD19 CAR T-cell therapy has transformed the treatment landscape for patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL), producing durable remissions in many patients. However, nearly half of patients eventually experience disease progression, highlighting the need to better understand mechanisms of resistance.
In this study, investigators identified folate receptor beta (FRβ) as a marker of immunosuppressive M2-like tumor-associated macrophages (TAMs), a key component of the lymphoma tumor microenvironment (TME). Higher FRβ expression was associated with inferior survival across multiple independent DLBCL cohorts.
Using lymphoma – macrophage spheroid models, researchers uncovered a bidirectional relationship between lymphoma cells and TAMs:
- Lymphoma cells promoted monocyte differentiation into immunosuppressive M2-like macrophages.
- M2-like macrophages enhanced lymphoma growth and reduced CD19 CAR T-cell-mediated killing.
- TAMs drove CAR T cells toward an exhausted phenotype, contributing to therapeutic resistance.
To overcome this barrier, the investigators engineered FRβ-targeted CAR T cells designed to eliminate M2-like macrophages before CD19 CAR T-cell therapy. In preclinical models, sequential targeting of TAMs followed by CD19 CAR T cells improved lymphoma killing.
These findings highlight that CAR T-cell failure is not solely a tumor-cell problem – the surrounding immune microenvironment plays a critical role. By targeting the immunosuppressive macrophage niche, FRβ CAR T cells may provide a strategy to enhance CAR T-cell persistence and efficacy in DLBCL.
The future of CAR T-cell therapy may not only involve making better T cells – but also remodeling the environment that prevents them from working.”
Title: Folate receptor beta targeting of tumor-associated macrophages improves lymphoma cell responses to CD19 CAR T cells
Authors: Kerttu Kalander, Katri Oksa, Selma Sorri, Hector Monzo, Suvi-Katri Leivonen, Päivi M. Ojala, Sirpa Leppä
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