CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome

Arcangeli, Silvia; Bove, Camilla; Mezzanotte, Claudia; Camisa, Barbara; Falcone, Laura; Manfredi, Francesco; Bezzecchi, Eugenia; Khoury, Rita El; Norata, Rossana; Sanvito, Francesca; Ponzoni, Maurilio; Greco, Béatrice; Moresco, Marta Angiola; Carrabba, Matteo Giovanni; Ciceri, Fabio; Bonini, Chiara; Bondanza, Attilio; Casucci, Monica

doi:10.1172/jci150807

Cited by 120 publications

(91 citation statements)

References 61 publications

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“…We found that CD4/CD8 ratio at apheresis showed a positive correlation with increased lymphocyte count at day 7 especially in the CD3 LOW group (data not shown). Furthermore, previous studies demonstrated that CAR T cell products generated from naïve/stem memory T cells, as compared with unselected T cells, shows superior antitumor activity and increase expansion rates 26 , 27 . However, because it is difficult to evaluate theses phenotypes in the clinical setting, we used lymphocyte counts in peripheral blood as a simple biomarker reflecting CAR-T cell proliferation 28 , 29 .…”

Section: Discussionmentioning

confidence: 99%

T-cell counts in peripheral blood at leukapheresis predict responses to subsequent CAR-T cell therapy

Wada

Arai

et al. 2022

Sci Rep

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Prediction of responses to chimeric antigen receptor (CAR)-T cell therapies is essential to maximize their therapeutic efficacy for diffuse large B-cell lymphoma (DLBCL). While several tumor-intrinsic risk factors of resistance and/or early relapse have been identified, clinically useful markers that determine potential activity of CAR-T cells have not been fully investigated. T-cell property at the time of leukapheresis may serve as such a marker. Therefore, we evaluated the clinical impact of CD3+ cell count in peripheral blood at leukapheresis on clinical outcomes of CAR-T cell therapy. In total, 44 patients with relapsed or refractory (r/r) DLBCL who received tisagenlecleucel at Kyoto University Hospital were included. According to CD3+ cell counts, patients were categorized into CD3LOW and CD3HIGH groups with a threshold of 553/μL, based on receiver operating characteristic curve analysis. 1-year progression-free survival was significantly higher in the CD3HIGH group than the CD3LOW group (68.3% vs. 17.3%; adjusted hazard ratio [aHR], 0.37; p = 0.042). Overall survival was also superior in the CD3HIGH group (aHR, 0.24; p = 0.043). Moreover, higher CD3+ cell counts at leukapheresis were associated with significantly higher lymphocyte counts in peripheral blood at day 7 after CAR-T cell infusion (median 860 vs. 420/μL, P = 0.021), suggesting more extensive expansion of infused CAR-T cells in vivo. In conclusion, we demonstrated that the CD3+ cell count at leukapheresis predicts both expansion of CAR-T cells after infusion and outcomes of CAR-T cell therapy, and are useful for building comprehensive therapeutic strategies at the time of leukapheresis.

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Section: Discussionmentioning

confidence: 99%

T-cell counts in peripheral blood at leukapheresis predict responses to subsequent CAR-T cell therapy

Wada

Arai

et al. 2022

Sci Rep

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“… 138 Similarly, CAR-T cells generated from pre-selected naive and stem cell memory T cells demonstrated superior and sustained anti-leukemia activity in a humanized mouse model compared with bulk CAR-T cells. 139 CAR-T SCM cells can be reliably generated at clinical scale and were tested in a clinical trial ( NCT01087294 ).…”

Section: Car-t Cell Biology and Animal Modelsmentioning

confidence: 99%

Applying a clinical lens to animal models of CAR-T cell therapies

Duncan¹,

Dunbar²,

Ishii³

2022

Molecular Therapy - Methods & Clinical Development

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“…Both the T-cell phenotype and T-cell subset in the starting material and final product were shown to influence the therapeutic efficacy of CAR-T cells. For instance, the application of defined ratios of T-cell subsets or manufacturing from naïve/stem memory T cells was shown to enhance anti-tumor reactivity and CAR-T persistence [ 12 , 30 , 31 ]. Hence, a better understanding of the synergistic effects of different T-cell subsets within the CAR-T product will help to improve the therapeutic efficacy.…”

Section: Resultsmentioning

confidence: 99%

“…Hence, a better understanding of the synergistic effects of different T-cell subsets within the CAR-T product will help to improve the therapeutic efficacy. To do so, state-of-the-art methods require the isolation of subpopulations, separate genetic modification, and the subsequent mixing of the cell products [ 12 , 30 , 31 , 32 ]. In contrast, targeted LVs can be used to transduce defined T-cell subsets within mixed populations.…”

Section: Resultsmentioning

confidence: 99%

“…Improving this production process could result in a CAR-T cell product with enhanced efficacy. For instance, a shorter ex vivo expansion phase and the transduction of naïve T-cell subsets was shown to increase CAR-T cell efficacy [ 11 , 12 ]. Ruella and colleagues showed that off-target transduction represents a major risk factor in CAR-T cell production, as the transduction of a single leukemic B cell led to resistance to CAR-T cells [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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Adapter-Mediated Transduction with Lentiviral Vectors: A Novel Tool for Cell-Type-Specific Gene Transfer

Cordes

Winter

Kolbe

et al. 2022

Viruses

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Selective gene delivery to a cell type of interest utilizing targeted lentiviral vectors (LVs) is an efficient and safe strategy for cell and gene therapy applications, including chimeric antigen receptor (CAR)-T cell therapy. LVs pseudotyped with measles virus envelope proteins (MV-LVs) have been retargeted by ablating binding to natural receptors while fusing to a single-chain antibody specific for the antigen of choice. However, the broad application of MV-LVs is hampered by the laborious LV engineering required for every new target. Here, we report the first versatile targeting system for MV-LVs that solely requires mixing with biotinylated adapter molecules to enable selective gene transfer. The analysis of the selectivity in mixed cell populations revealed transduction efficiencies below the detection limit in the absence of an adapter and up to 5000-fold on-to-off-target ratios. Flexibility was confirmed by transducing cell lines and primary cells applying seven different adapter specificities in total. Furthermore, adapter mixtures were applied to generate CAR-T cells with varying CD4/CD8-ratios in a single transduction step. In summary, a selective and flexible targeting system was established that may serve to improve the safety and efficacy of cellular therapies. Compatibility with a wide range of readily available biotinylated molecules provides an ideal technology for a variety of applications.

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CAR T cell manufacturing from naive/stem memory T lymphocytes enhances antitumor responses while curtailing cytokine release syndrome

Cited by 120 publications

References 61 publications

T-cell counts in peripheral blood at leukapheresis predict responses to subsequent CAR-T cell therapy

T-cell counts in peripheral blood at leukapheresis predict responses to subsequent CAR-T cell therapy

Applying a clinical lens to animal models of CAR-T cell therapies

Adapter-Mediated Transduction with Lentiviral Vectors: A Novel Tool for Cell-Type-Specific Gene Transfer

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