Combining CAR T-Cell Therapy and Nivolumab to Overcome Immune Resistance in THRLBCL: A Case Report
T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) is a rare, aggressive subtype of diffuse large B-cell lymphoma characterized by a profoundly immunosuppressive tumor microenvironment. PD-L1 overexpression by tumor cells is a recognized immune escape mechanism and may underlie resistance to cellular therapies, including CAR T-cell therapy. We report a case of a 29-year-old woman with refractory stage IV-B THRLBCL treated with anti-CD19 CAR T-cell therapy (varnimcabtagene autoleucel), who achieved an initial response (day +28) but experienced disease progression by day +100 despite robust CAR T-cell expansion. Peripheral blood analysis revealed persistent absolute B-cell aplasia, while bone marrow biopsy confirmed CD19-positive disease. Comparative immunohistochemistry demonstrated markedly increased PD-L1 expression in post-CAR T-cell samples, suggesting adaptive immune resistance via PD-1/PD-L1-mediated CAR T-cell inhibition. Nivolumab was initiated at month +4 to overcome this checkpoint-mediated resistance. Notably, a complete metabolic response was documented on PET/CT after four doses of nivolumab (month +6). The patient remains in sustained remission, with persistent B-cell aplasia, four years post-intervention. This case provides clinical and pathological evidence supporting the use of immune checkpoint blockade to rescue CAR T-cell efficacy, highlighting the potential of this synergistic approach in THRLBCL and possibly other B-cell malignancies exhibiting similar immune evasion.
Authors
- Andrea Rivero (ORCID: https://orcid.org/0000-0002-4233-5031)
- Nil Albiol (ORCID: https://orcid.org/0000-0003-2942-1362)
- Jordi Esteve
- Álvaro Urbano-Ispizúa (ORCID: https://orcid.org/0000-0002-7529-9399)
- Alexandra Martínez‐Roca (ORCID: https://orcid.org/0000-0003-2143-5356)
- Oriana López‐Godino (ORCID: https://orcid.org/0009-0000-9637-6042)
- Luis Gerardo Rodríguez‐Lobato (ORCID: https://orcid.org/0000-0001-5694-0921)
- Marta Español‐Rego (ORCID: https://orcid.org/0000-0001-5497-2276)
- Juan Gonzalo Correa (ORCID: https://orcid.org/0000-0001-6470-8102)
- Helena Brillembourg
- Guillermo Muñoz‐Sánchez (ORCID: https://orcid.org/0000-0002-0308-6255)
- Valentín Ortiz‐Maldonado (ORCID: https://orcid.org/0000-0003-4699-6862)
- Eva Giné (ORCID: https://orcid.org/0000-0002-0532-1204)
- Pablo Mozas (ORCID: https://orcid.org/0000-0001-9528-4971)
- Sergio Navarro‐Velázquez (ORCID: https://orcid.org/0000-0002-5565-4218)
- Europa Azucena González‐Navarro (ORCID: https://orcid.org/0000-0003-3310-5557)
- Manel Juan (ORCID: https://orcid.org/0000-0002-3064-1648)
- Sebastián Casanueva-Eliceiry (ORCID: https://orcid.org/0000-0002-5539-5850)
- Letícia Alserawan (ORCID: https://orcid.org/0000-0003-0428-9844)
- Mercedes Montoro-Lorite
- Laura Magnano (ORCID: https://orcid.org/0000-0002-6928-8386)
- Núria Martínez‐Cibrián (ORCID: https://orcid.org/0000-0002-8688-1202)
- Daniel Benítez‐Ribas (ORCID: https://orcid.org/0000-0002-2346-5324)
- Daniel Munárriz
- Laura Frutos (ORCID: https://orcid.org/0000-0003-2128-9504)
- Pilar Ayora
- Julio Delgado
- Olga Balagué-Ponz
- Lucía García-Tomás
Institutions
- Hospital Sant Joan de Déu Barcelona (ES)
- Fred Hutch Cancer Center (US)
- Josep Carreras Leukaemia Research Institute (ES)
- Hospital Clínic de Barcelona (ES)
- Centro Regional de Hemodonación (ES)
- Sant Joan de Déu Research Foundation (ES)
- Hospital Universitario Virgen de la Arrixaca (ES)
- Consorci Institut D'Investigacions Biomediques August Pi I Sunyer (ES)
- Universitat de Barcelona (ES)
Publication Details
- Journal
- International Journal of Molecular Sciences
- Published
- 2025-09-23
- DOI
- https://doi.org/10.3390/ijms26199265
- Citations
- 3
- Primary Topic
- CAR-T cell therapy research
- Type
- article
- Field-Weighted Citation Impact
- 3.14