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Torque Teno Virus plasma DNA load: a novel prognostic biomarker in CAR-T therapy

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Abstract

Torque Teno Virus (TTV) is a single-stranded circular DNA virus which has been identified as a surrogate marker of immune competence in transplantation. In this study we investigated the dynamics of plasma TTV DNAemia in 79 adult patients undergoing chimeric antigen receptor T-cell (CAR-T) therapy for relapsed or refractory large B-cell lymphoma, also evaluating the impact of TTV on immunotoxicities, response and survival outcomes. After lymphodepleting therapy, TTV DNA load was found to decrease slightly until reaching nadir around day 10, after which it increased steadily until reaching maximum load around day 90. TTV DNA load < 4.05 log10 copies/ml at immune effector cell-associated neurotoxicity syndrome (ICANS) onset identified patients at risk of progressing to severe forms of ICANS (OR 16.68, P = 0.048). Finally, patients who experienced falling or stable TTV DNA load between lymphodepletion and CAR-T infusion had better progression-free survival than those with ascending TTV DNA load (HR 0.31, P = 0.006). These findings suggest that TTV monitoring could serve as a surrogate marker of immune competence, enabling predictions of CAR-T efficacy and toxicity. This could pave the way for the development of TTV-guided therapeutic strategies that modulate clinical patient management based on plasma TTV load, similar to suggested strategies in solid organ transplant recipients.

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Fig. 1: Dynamics of TTV DNAemia in plasma over the study period.
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The data used to support the findings of this study are included within the article and its Supplementary material.

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Acknowledgements

The Institut Paoli-Calmettes (Marseille, France) was also included as a collaborating center. The study was classified as a clinical trial in France (NCT04822974). Unfortunately, the implementation of the study in France was prevented by the COVID-19 pandemic. All authors would like to express their gratitude to these colleagues in Marseille, especially Prof. Didier Blaise and Dr. Raynier Devillier.

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Author notes

  1. These authors contributed equally: Ana Benzaquén, Rafael Hernani.

Authors and Affiliations

  1. Haematology Department, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain

    Ana Benzaquén, Rafael Hernani, Ariadna Pérez, José Luis Piñana, Juan Carlos Hernández-Boluda, Blanca Ferrer, Paula Amat, Diana Campos, María José Terol & Carlos Solano

  2. Microbiology Department, Hospital Clínico Universitario, INCLIVA Research Institute, Valencia, Spain

    Estela Giménez, Eliseo Albert, Carlos S de la Asunción & David Navarro

  3. Haematology Department, Hospital Universitari Vall d’Hebron, Barcelona, Spain

    Gloria Iacoboni, Cecilia Carpio, Mario Andrés Sánchez-Salinas, Francisco Beas & Pere Barba

  4. Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain

    Gloria Iacoboni & Pere Barba

  5. Haematology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain

    Manuel Guerreiro, Aitana Balaguer, Pedro Chorão, Juan Montoro, Ana Facal, Marta Villalba & Jaime Sanz

  6. Department of Medicine, University of Valencia, Valencia, Spain

    Juan Carlos Hernández-Boluda, Paula Amat, María José Terol, Jaime Sanz & Carlos Solano

  7. Department of Microbiology, University of Valencia, Valencia, Spain

    David Navarro

  8. Centro de Investigación Biomédica en Red de Enfermedades Infecciosas (CIBERINFEC), Instituto de Salud Carlos III, Madrid, Spain

    David Navarro

  9. Microbiology Department, Hospital Universitari i Politècnic La Fe, Valencia, Spain

    María Dolores Goméz

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  1. Ana Benzaquén
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Contributions

AB, EG, and RH conceived the study and interpreted the data; AB and RH wrote the paper; AB, RH and EA performed the statistical analyses; EG, GI, MG, EA, CC, AB, AP, CSA, MASS, PC, JLP, FB, JM, JCHB, AF, BF, MV, PA, DC, MJT, JS, PB, DN, and CS reviewed the paper and contributed to the final draft.

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Correspondence to Pere Barba.

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Competing interests

A Gilead grant (Beca FEHH-GILEAD para Formación en Investigación en Terapia Celular en un centro internacional Convocatoria 2019) was awarded to AB. RH was the principal investigator of the grant-associated study. The authors declare no competing interests.

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Benzaquén, A., Giménez, E., Iacoboni, G. et al. Torque Teno Virus plasma DNA load: a novel prognostic biomarker in CAR-T therapy. Bone Marrow Transplant 59, 93–100 (2024). https://doi.org/10.1038/s41409-023-02114-0

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