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Optimization of CAR T-cell dose: a debated unresolved issue

Bone Marrow Transplantation (2025)Cite this article

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Chimeric antigen receptor (CAR) T-cells are incredibly potent in killing tumor cells and have been extraordinarily successful in putting hematologic patients into remission. However, several challenges accompany them including severe side-effects, such as cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), and high relapse rates [1, 2]. This immunotherapy targets both to tumor reduction and activate a long-lasting anti-tumor response. A successful outcome would depend on a balance between robust anti-tumor activity while sparing detrimental side effects. Failure factors include inadequate in vivo expansion, limited CAR T-cell persistence due to exhaustion and antigen loss [3].

CAR T-cells can be considered as “living drugs” because they consist of live cells which have the ability of ex νiνο and in vivo proliferation - differentiation. Upon antigen engagement, they undergo a marked rapid exponential proliferation which can reach from 100–100 000 fold, while they can be detected even for years [1]. They do not only proliferate and expand but also retain the cytotoxic function of activated T-cells [4]. As “living drugs” they present different bioavailability characteristics compared to classical pharmacological molecules. Kinetic and dynamic parameters of a conventional drug e.g. AUC, Cmax, Tmax, T1/2, etc largely depend on the initial drug concentration and their action can be described by certain pharmacokinetic/pharmacodynamic models. CAR T-cells cannot follow these typical models as their kinetics and function are difficult to be foreseen and captured [5]. A CAR T-cell product could be considered a “living multi-drug”, because each cell type has its own kinetic and dynamic parameters. It is impossible to achieve the same therapeutic outcome from two autologous CAR T-cell products with simply the same initial cell number.

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Fig. 1: Model for determining the optimal therapeutic dose in CAR T-cell personalized therapies “Do not keep moving forward but take the reverse pathway”.

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Authors and Affiliations

  1. BReMeL, Biopharmaceutical and Regenerative Medicine Laboratories, Thessaloniki, 55534, Greece

    Dimitrios Bouzianas

  2. Comprehensive Cancer Centre, School of Cancer and Pharmaceutical Medicine, King’s College London, London, SE5 8AF, UK

    Stella Bouziana

  3. Department of Haematology, King’s College Hospital National Health Service (NHS) Foundation Trust, London, SE5 9RS, UK

    Stella Bouziana

Authors
  1. Dimitrios Bouzianas
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  2. Stella Bouziana
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DB and SB contributed to conception and design; DB drafted the original manuscript; SB revised and edited it and designed the figure. Both authors read and approved the final manuscript. Both authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

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Correspondence to Dimitrios Bouzianas or Stella Bouziana.

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Bouzianas, D., Bouziana, S. Optimization of CAR T-cell dose: a debated unresolved issue. Bone Marrow Transplant (2025). https://doi.org/10.1038/s41409-025-02662-7

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