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Review
. 2023 Dec 22:14:1303935.
doi: 10.3389/fimmu.2023.1303935. eCollection 2023.

Lymphodepletion - an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle

Benno Lickefett  1 , Lulu Chu  2 , Valentin Ortiz-Maldonado  3 , Linda Warmuth  4 , Pere Barba  5 , Matteo Doglio  6 , David Henderson  7 , Michael Hudecek  8 , Andreas Kremer  9 , Janet Markman  2 , Magdalena Nauerth  4 , Helene Negre  10 , Carmen Sanges  8 , Philipp B Staber  1 , Rebecca Tanzi  10 , Julio Delgado  3 , Dirk H Busch  4 , Jürgen Kuball  11 , Maik Luu  8 , Ulrich Jäger  1
Affiliations
Review

Lymphodepletion - an essential but undervalued part of the chimeric antigen receptor T-cell therapy cycle

Benno Lickefett et al. Front Immunol. .

Abstract

Lymphodepletion (LD) or conditioning is an essential step in the application of currently used autologous and allogeneic chimeric antigen receptor T-cell (CAR-T) therapies as it maximizes engraftment, efficacy and long-term survival of CAR-T. Its main modes of action are the depletion and modulation of endogenous lymphocytes, conditioning of the microenvironment for improved CAR-T expansion and persistence, and reduction of tumor load. However, most LD regimens provide a broad and fairly unspecific suppression of T-cells as well as other hematopoietic cells, which can also lead to severe side effects, particularly infections. We reviewed 1271 published studies (2011-2023) with regard to current LD strategies for approved anti-CD19 CAR-T products for large B cell lymphoma (LBCL). Fludarabine (Flu) and cyclophosphamide (Cy) (alone or in combination) were the most commonly used agents. A large number of different schemes and combinations have been reported. In the respective schemes, doses of Flu and Cy (range 75-120mg/m2 and 750-1.500mg/m2) and wash out times (range 2-5 days) differed substantially. Furthermore, combinations with other agents such as bendamustine (benda), busulfan or alemtuzumab (for allogeneic CAR-T) were described. This diversity creates a challenge but also an opportunity to investigate the impact of LD on cellular kinetics and clinical outcomes of CAR-T. Only 21 studies explicitly investigated in more detail the influence of LD on safety and efficacy. As Flu and Cy can potentially impact both the in vivo activity and toxicity of CAR-T, a more detailed analysis of LD outcomes will be needed before we are able to fully assess its impact on different T-cell subsets within the CAR-T product. The T2EVOLVE consortium propagates a strategic investigation of LD protocols for the development of optimized conditioning regimens.

Keywords: CAR-T cells; conditioning; efficacy; lymphodepletion; optimization; toxicity.

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Conflict of interest statement

MH and ML: inventors on patents related to CAR T- cell therapy filed by the University of Würzburg. MH is listed as an inventor on patent applications and granted patents related to CAR-T technologies that have been filed by the Fred Hutchinson Cancer Research Center, Seattle, WA and by the University of Würzburg, Würzburg, Germany. MH is a co-founder and equity owner of T-CURX GmbH, Würzburg, Germany. MH received honoraria from Celgene/BMS, Janssen, Kite/Gilead. VO-M: Travel grants: Kite, Celgene-BMS, Novartis, Roche, Takeda & Janssen; Consultant or advisory fees: Kite, Celgene-BMS, Miltenyi Biomedicine, Pfizer, Novartis & Janssen; Honoraria: Kite, Celgene-BMS & Janssen; Employment: Hospital Clínic de Barcelona. UJ: consultant and advisory fees from Novartis, BMS, Gilead, Janssen, Roche, Honoraria from Miltenyi Biomedicine. DB: research projects with Juno/BMS and Repairon Immuno GmbH; consultant and advisory fees from BMS and Immatics. JD: Employment: Hospital Clínic de Barcelona. DH is an employee and shareholder of Bayer AG. HN and RT: are employees of Servier IRIS. PB: Advisory Board and consultancy from Allogene, Amgen, BMS/Celgene, Kite/Gilead, Incyte, Miltenyi Biomedicine, Novartis, Nektar, Pfizer and Pierre FabreKite/Gilead, Incyte, Miltenyi Biomedicine, Novartis, Nektar, Pfizer and Pierre Fabre. JK: Received grants form Novartis, Miltenyi Biotech and Gadeta. JK is inventor and receives revenues on multiple patents on CAR T and TEG engineering. LC was employed by Takeda. AK was employed by ITTM S.A. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

Figure 1
Figure 1
Major effects of lymphodepleting therapy on the host. LD influences (1) number and composition of host lymphocytes as well as cytokine production; (2) reduces the tumor and modulates its behavior; (3) reprograms the host microenvironment for better homing of CAR-T cells.
Figure 2
Figure 2
Cellular kinetics after lymphodepletion: (A) Profound decrease in host PB hematopoietic precursor cells. A marked drop in common myeloid progenitors CFU-GEMM (orange line) is observed between LD (red vertical bar) and CAR-T infusion in parallel with PB leukocyte counts (blue line) (patient example); (B) Kinetics of CAR-T cells is dependent on the intensity of LD. This is accompanied by an improved survival.
See this image and copyright information in PMC

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