Association between CAR T-cell persistence and improved response to salvage radiotherapy in patients with DLBCL

Authors

  • Jiaqi Fan Department of Radiation Oncology, Cyberknife and Radiation Therapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany https://orcid.org/0009-0002-8418-3192
  • Nadine Kutsch Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany https://orcid.org/0000-0001-9559-8575
  • Jan-Michel Heger Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany; Cancer Center Cologne Essen, Partner Site Cologne, Cologne, Germany; Cologne Lymphoma Working Group (CLWG), Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany
  • Philipp Gödel Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany
  • Eva Heger Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany https://orcid.org/0000-0001-7625-5139
  • Henning Gruell Institute of Virology, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; German Center for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany https://orcid.org/0000-0002-0725-7138
  • Philipp Linde Department of Radiation Oncology, Cyberknife and Radiation Therapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • Simone Ferdinandus Department of Radiation Oncology, Cyberknife and Radiation Therapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • Johannes Rosenbrock Department of Radiation Oncology, Cyberknife and Radiation Therapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • Hendrik Dapper Department of Radiation Oncology, Cyberknife and Radiation Therapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • Emmanouil Fokas Department of Radiation Oncology, Cyberknife and Radiation Therapy, Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany
  • Peter Borchmann Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf, University of Cologne, Medical Faculty and University Hospital Cologne, Cologne, Germany https://orcid.org/0000-0003-3782-2158
  • Christian Baues Department of Radiation Oncology, Marienhospital Herne, Ruhr University Bochum, Bochum, Germany

DOI:

https://doi.org/10.2340/1651-226X.2026.46287

Keywords:

lymphoma, large B-cell, diffuse, Immunotherapy, adoptive, CAR T-cell therapy, salvage radiotherapy

Abstract

Background and purpose: While Chimeric antigen receptor (CAR) T-cell therapy has transformed treatment of relapsed/refractory diffuse large B-cell lymphoma (DLBCL), over half of patients relapse within 1 year with poor prognosis. Salvage radiotherapy (sRT) achieves high local response rates, but which subgroups benefit most and whether CAR T-cell persistence influences sRT response remains unclear.

Patient/material and methods: We retrospectively analyzed DLBCL patients receiving sRT after CAR T-cell therapy at our center. CAR transgene levels were quantified by quantitative polymerase chain reaction (qPCR), and associations between CAR T-cell kinetics at relapse, sRT response, and survival were evaluated.

Results: CAR transgene data were available for 13 patients, (18 lesions treated with sRT). Toxicity was mild (grade ≤ 2). The local response rate was 83% (15/18 lesions). Three CAR transgene kinetic patterns were identified at relapse: increased-CAR (second increase in transgene levels, n = 4), persisted-CAR (persistence > 6 months, n = 4), and decreased-CAR (decline or absence, n = 5). Local response rates were 100% in both the increased- and persisted-CAR groups versus 57% (4/7 lesions) in the decreased-CAR group, 12-month local control rates were 83, 100, and 14%, respectively. Twelve-month overall survival was 100% in both increased-CAR and persisted-CAR groups versus 20% in the decreased-CAR group.

Interpretation: sRT may provide durable local control in relapsed DLBCL after CAR T-cell therapy. Persistent CAR T-cell activity at relapse may help identify patients most likely to benefit from comprehensive sRT. Given the small, heterogeneous cohort, these findings are hypothesis-generating and require validation in larger series.

Downloads

Download data is not yet available.

References

Locke FL, Siddiqi T, Jacobson CA, Ghobadi A, Ahmed S, Miklos DB, et al. Real-world and clinical trial outcomes in large B-cell lymphoma with axicabtagene ciloleucel across race and ethnicity. Blood. 2024;143(26):2722–34. DOI: https://doi.org/10.1182/blood.2023023447

Jacobson CA, Munoz J, Sun F, Kanters S, Limbrick-Oldfield EH, Spooner C, et al. Real-world outcomes with chimeric antigen receptor T cell therapies in large B cell lymphoma: a systematic review and meta-analysis. Transpl Cell Ther. 2024;30(1):77.e1–77.e15. DOI: https://doi.org/10.1016/j.jtct.2023.10.017

Landsburg DJ, Frigault MJ, Heim M, Foley SR, Hill B, Schofield G, et al. Real-world outcomes with tisagenlecleucel in aggressive B-cell lymphoma: subgroup analyses from the CIBMTR registry. J Immunother Cancer. 2025;13(2):e009890. DOI: https://doi.org/10.1136/jitc-2024-009890

Di Blasi R, Le Gouill S, Bachy E, Cartron G, Beauvais D, Le Bras F, et al. Outcomes of patients with aggressive B-cell lymphoma after failure of anti-CD19 CAR T-cell therapy: a DESCAR-T analysis. Blood. 2022;140(24):2584–93. DOI: https://doi.org/10.1182/blood.2022016945

Alarcon Tomas A, Fein JA, Fried S, Flynn JR, Devlin SM, Fingrut WB, et al. Outcomes of first therapy after CD19-CAR-T treatment failure in large B-cell lymphoma. Leukemia. 2023;37(1):154–63. DOI: https://doi.org/10.1038/s41375-022-01739-2

Iacoboni G, Iraola-Truchuelo J, O’Reilly M, Navarro V, Menne T, Kwon M, et al. Treatment outcomes in patients with large B-cell lymphoma after progression to chimeric antigen receptor T-cell therapy. Hemasphere. 2024;8(5):e62. DOI: https://doi.org/10.1002/hem3.62

Imber BS, Sadelain M, DeSelm C, Batlevi C, Brentjens RJ, Dahi PB, et al. Early experience using salvage radiotherapy for relapsed/refractory non-Hodgkin lymphomas after CD19 CAR T-cell therapy. Br J Haematol. 2020;190(1):45–51. DOI: https://doi.org/10.1111/bjh.16541

Saifi O, Breen WG, Lester SC, Rule WG, Stish BJ, Rosenthal A, et al. Consolidative radiotherapy for residual fluorodeoxyglucose activity on day +30 post CAR T-cell therapy in non-Hodgkin lymphoma. Haematologica. 2023;108(11):2982–92. DOI: https://doi.org/10.3324/haematol.2023.283311

Fan J, Adams A, Sieg N, Heger JM, Gödel P, Kutsch N, et al. Potential synergy between radiotherapy and CAR T-cells – a multicentric analysis of the role of radiotherapy in the combination of CAR T cell therapy. Radiother Oncol. 2023;183:109580. DOI: https://doi.org/10.1016/j.radonc.2023.109580

Ababneh HS, Ng AK, Frigault MJ, Abramson JS, Johnson PC, Jacobson CA, et al. Salvage radiotherapy in relapsed/refractory large B-cell lymphoma after failure of CAR T-cell therapy. Haematologica. 2023;108(11):2972–81. DOI: https://doi.org/10.3324/haematol.2023.282804

Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the lugano classification. J Clin Oncol. 2014;32(27):3059–67. DOI: https://doi.org/10.1200/JCO.2013.54.8800

National Cancer Institute. Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0. U.S. Department of Health and Human Services, National Institutes of Health; 2017. Published November 27, 2017.

van Duin M, Snijders PJF, Schrijnemakers HFJ, Voorhorst FJ, Rozendaal L, Nobbenhuis MAE, et al. Human papillomavirus 16 load in normal and abnormal cervical scrapes: an indicator of CIN II/III and viral clearance. Int J Cancer. 2002;98(4):590–5. DOI: https://doi.org/10.1002/ijc.10232

Saifi O, Breen WG, Lester SC, Rule WG, Stish B, Rosenthal A, et al. Does bridging radiation therapy affect the pattern of failure after CAR T-cell therapy in non-Hodgkin lymphoma? Radiother Oncol. 2022;166:171–9. DOI: https://doi.org/10.1016/j.radonc.2021.11.031

Ababneh HS, Ng AK, Frigault MJ, Jacobson CA, Patel CG. Radiotherapy as a bridging strategy for patients with relapsed or refractory large B-cell lymphoma undergoing CAR T-cell therapy. Am J Hematol. 2024;99(9):1837–40. DOI: https://doi.org/10.1002/ajh.27409

Hubbeling H, Silverman EA, Michaud L, Tomas AA, Shouval R, Flynn J, et al. Bridging radiation rapidly and effectively cytoreduces high-risk relapsed/refractory aggressive B cell lymphomas prior to chimeric antigen receptor T cell therapy. Transpl Cell Ther. 2023;29(4):259.e1–10. DOI: https://doi.org/10.1016/j.jtct.2022.12.021

DeSelm C, Palomba ML, Yahalom J, Hamieh M, Eyquem J, Rajasekhar VK, et al. Low-dose radiation conditioning enables CAR T cells to mitigate antigen escape. Mol Ther. 2018;26(11):2542–52. DOI: https://doi.org/10.1016/j.ymthe.2018.09.008

Weiss T, Weller M, Guckenberger M, Sentman CL, Roth P. NKG2D-based CAR T cells and radiotherapy exert synergistic efficacy in glioblastoma. Cancer Res. 2018;78(4):1031–43. DOI: https://doi.org/10.1158/0008-5472.CAN-17-1788

Murty S, Haile ST, Beinat C, Aalipour A, Alam IS, Murty T, et al. Intravital imaging reveals synergistic effect of CAR T-cells and radiation therapy in a preclinical immunocompetent glioblastoma model. Oncoimmunology. 2020;9(1):1757360. DOI: https://doi.org/10.1080/2162402X.2020.1757360

Kim AB, Chou SY, Kang S, Kwon E, Inkman M, Szymanski J, et al. Intrinsic tumor resistance to CAR T cells is a dynamic transcriptional state that is exploitable with low-dose radiation. Blood Adv. 2023;7(18):5396–408. DOI: https://doi.org/10.1182/bloodadvances.2022009543

Zhou M, Chen M, Shi B, Di S, Sun R, Jiang H, et al. Radiation enhances the efficacy of EGFR-targeted CAR-T cells against triple-negative breast cancer by activating NF-κB/Icam1 signaling. Mol Ther. 2022;30(11):3379–93. DOI: https://doi.org/10.1016/j.ymthe.2022.07.021

Singh N, Lee YG, Shestova O, Ravikumar P, Hayer KE, Hong SJ, et al. Impaired death receptor signaling in leukemia causes antigen-independent resistance by inducing CAR T cell dysfunction. Cancer Discov. 2020;10(4):552–67. DOI: https://doi.org/10.1158/2159-8290.CD-19-0813

Wittibschlager V, Bacher U, Seipel K, Porret N, Wiedemann G, Haslebacher C, et al. CAR T-cell persistence correlates with improved outcome in patients with B-cell lymphoma. Int J Mol Sci. 2023;24(6):5688. DOI: https://doi.org/10.3390/ijms24065688

Locke FL, Rossi JM, Neelapu SS, Jacobson CA, Miklos DB, Ghobadi A, et al. Tumor burden, inflammation, and product attributes determine outcomes of axicabtagene ciloleucel in large B-cell lymphoma. Blood Adv. 2020;4(19):4898–911. DOI: https://doi.org/10.1182/bloodadvances.2020002394

Gomez-Llobell M, Shouval R, Brown S, Goan-Accav N, Devlin S, Corona M, et al. Landmark-based evaluations of long-term outcomes after CD19 CAR T-cell therapy in large B-cell lymphoma. Transpl Cell Ther. 2026;32(6):676.e1–14. DOI: https://doi.org/10.1016/j.jtct.2026.02.058

Downloads

Published

2026-09-17

How to Cite

Fan, J., Kutsch, N., Heger, J.-M., Gödel, P., Heger, E., Gruell, H., … Baues, C. (2026). Association between CAR T-cell persistence and improved response to salvage radiotherapy in patients with DLBCL. Acta Oncologica, 65, 749–757. https://doi.org/10.2340/1651-226X.2026.46287

Issue

Vol. 65 (2026): Acta Oncologica

Section

Original article

Categories

License

Copyright (c) 2026 Jiaqi Fan, Nadine Kutsch, Jan-Michel Heger, Philipp Gödel, Eva Heger, Henning Gruell, Philipp Linde, Simone Ferdinandus, Johannes Rosenbrock, Hendrik Dapper, Emmanouil Fokas, Peter Borchmann, Christian Baues

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 International License.