Journal of Experimental & Clinical Cancer Research (Sep 2024)

In vivo CAR T cell therapy against angioimmunoblastic T cell lymphoma

  • Adrien Krug,
  • Aymen Saidane,
  • Chiara Martinello,
  • Floriane Fusil,
  • Alexander Michels,
  • Christian J. Buchholz,
  • Jean-Ehrland Ricci,
  • Els Verhoeyen

DOI
https://doi.org/10.1186/s13046-024-03179-5
Journal volume & issue
Vol. 43, no. 1
pp. 1 – 18

Abstract

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Abstract Background For angioimmunoblastic T cell lymphoma (AITL), a rare cancer, no specific treatments are available and survival outcome is poor. We previously developed a murine model for AITL that mimics closely human disease and allows to evaluate new treatments. As in human AITL, the murine CD4+ follicular helper T (Tfh) cells are drivers of the malignancy. Therefore, chimeric antigen receptor (CAR) T cell therapy might represent a new therapeutic option. Methods To prevent fratricide among CAR T cells when delivering an CD4-specific CAR, we used a lentiviral vector (LV) encoding an anti-CD4 CAR, allowing exclusive entry into CD8 T cells. Results These anti-CD4CAR CD8-targeted LVs achieved in murine AITL biopsies high CAR-expression levels in CD8 T cells. Malignant CD4 Tfh cells were eliminated from the mAITL lymphoma, while the CAR + CD8 T cells expanded upon encounter with the CD4 receptor and were shaped into functional cytotoxic cells. Finally, in vivo injection of the CAR + CD8-LVs into our preclinical AITL mouse model carrying lymphomas, significantly prolonged mice survival. Moreover, the in vivo generated functional CAR + CD8 T cells efficiently reduced neoplastic T cell numbers in the mAITL tumors. Conclusion This is the first description of in vivo generated CAR T cells for therapy of a T cell lymphoma. The strategy described offers a new therapeutic concept for patients suffering from CD4-driven T cell lymphomas.

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