Interleukin-18 Secreting Autologous Anti-CD19 CAR T-Cells (huCART19-IL18) in Patients with Non-Hodgkin Lymphomas Relapsed or Refractory to Prior CAR T-Cell Therapy

Svoboda, Jakub; Gerson, James N.; Landsburg, Daniel J.; Chong, Elise A.; Barta, Stefan K.; Nasta, Sunita Dwivedy; Ruella, Marco; Hexner, Elizabeth O.; Marshall, Amy; Leskowitz, Rachel; Four, Megan; Shea, Joanne; Matlawski, Tina; Cervini, Amanda; Davis, Megan M.; Gohil, Mercy; Scholler, John; Hasenmayer, D.; Amortegui, Juliana Rojas; Brennan, Andrea; Plesa, Gabriela; Hwang, Wei–Ting; Porter, David L.; Fraietta, Joseph A.; Schuster, Stephen J.; June, Carl H.

doi:10.1182/blood-2022-162393

Cited by 30 publications

(16 citation statements)

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“…Similarly, the safety profile of IL-18–secreting CAR T cells will need to be studied. Importantly, no increase in IL-6, a cytokine associated with cytokine release syndrome, was observed in a murine CD19_mIL18 model ( 20 ), and no safety concerns were reported in the first patients that received huCART19-IL18 ( 25 ).…”

Section: Discussionmentioning

confidence: 99%

IL-18–secreting CAR T cells targeting DLL3 are highly effective in small cell lung cancer models

Jaspers¹,

Khan²,

Godfrey³

et al. 2023

Journal of Clinical Investigation

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Kowa, Lilly, Merck, and Syros. He serves on the scientific advisory boards of Bridge Medicines, Earli, and Harpoon Therapeutics. RJB has licensed intellectual property to and collect royalties from BMS, Caribou and Sanofi and received research funding from BMS. RJB is a consultant to BMS, Atara Biotherapeutics Inc, Coimmune, Triumvira and was a consultant for Gracell Biotechnologies Inc but ended employment in the past 24 months. RJB is a member of the scientific advisory board for CoImmune and Triumvira, and has ownership interest (including patents) in IL-18. No potential conflicts of interest were disclosed by the other authors.

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Section: Discussionmentioning

confidence: 99%

IL-18–secreting CAR T cells targeting DLL3 are highly effective in small cell lung cancer models

Jaspers¹,

Khan²,

Godfrey³

et al. 2023

Journal of Clinical Investigation

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“…In addition, continued efforts aim to further shorten the engineered T cell manufacturing process, which has been shown to improve T cell activity and persistence but could result in higher levels of chromosome loss. 45 To date, no study has investigated Cas9-induced chromosome loss in a clinical setting. In order to determine clinical significance, we generated CAR T cells using Cas9-mediated HDR, an approach being used in a growing number of clinical trials, 8,9 and found a significant enrichment in chromosome loss compared to non-targeted cells.…”

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells

Tsuchida

Brandes

Bueno

et al. 2023

Preprint

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CRISPR-Cas9 genome editing has enabled advanced T cell therapies, but occasional loss of the targeted chromosome remains a safety concern. To investigate whether Cas9-induced chromosome loss is a universal phenomenon and evaluate its clinical significance, we conducted a systematic analysis in primary human T cells. Arrayed and pooled CRISPR screens revealed that chromosome loss was generalizable across the genome and resulted in partial and entire loss of the chromosome, including in pre-clinical chimeric antigen receptor T cells. T cells with chromosome loss persisted for weeks in culture, implying the potential to interfere with clinical use. A modified cell manufacturing process, employed in our first-in-human clinical trial of Cas9-engineered T cells,1 dramatically reduced chromosome loss while largely preserving genome editing efficacy. Expression of p53 correlated with protection from chromosome loss observed in this protocol, suggesting both a mechanism and strategy for T cell engineering that mitigates this genotoxicity in the clinic.

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“…Svoboda and colleagues reported therapeutic doses in the range of 3 × 10 6 to 30 × 10 6 CAR T cells in patients with R/R NHL (NCT04684563) using IL18 secreting autologous 19.BBζ CAR T cells (huCART19-IL18; ref. 130 ). The FasT CAR-T (F-CAR-T) manufacturing platform in which T cell culture time is less than 24 hours was evaluated in two phase I clinical studies in patients with B-ALL using either CD19 or 19.22 Dual-CAR T cells (NCT03825718 and NCT04129099).…”

Section: Advances In T Cell Manufacturingmentioning

confidence: 99%

Programming CAR T Cell Tumor Recognition: Tuned Antigen Sensing and Logic Gating

et al. 2023

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The success of chimeric antigen receptor (CAR) T cells targeting B-cell malignancies propelled the field of synthetic immunology and raised hopes to treat solid tumors in a similar fashion. Antigen escape and the paucity of tumor-restricted CAR targets are recognized challenges to fulfilling this prospect. Recent advances in CAR T cell engineering extend the toolbox of chimeric receptors available to calibrate antigen sensitivity and combine receptors to create adapted tumor-sensing T cells. Emerging engineering strategies to lower the threshold for effective antigen recognition, when needed, and enable composite antigen recognition hold great promise for overcoming tumor heterogeneity and curbing off-tumor toxicities. Significance: Improving the clinical efficacy of CAR T cell therapies will require engineering T cells that overcome heterogeneous and low-abundance target expression while minimizing reactivity to normal tissues. Recent advances in CAR design and logic gating are poised to extend the success of CAR T cell therapies beyond B-cell malignancies.

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Interleukin-18 Secreting Autologous Anti-CD19 CAR T-Cells (huCART19-IL18) in Patients with Non-Hodgkin Lymphomas Relapsed or Refractory to Prior CAR T-Cell Therapy

Cited by 30 publications

References 0 publications

IL-18–secreting CAR T cells targeting DLL3 are highly effective in small cell lung cancer models

IL-18–secreting CAR T cells targeting DLL3 are highly effective in small cell lung cancer models

Mitigation of chromosome loss in clinical CRISPR-Cas9-engineered T cells

Programming CAR T Cell Tumor Recognition: Tuned Antigen Sensing and Logic Gating

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