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Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality

Author

Listed:
  • Mohit Sachdeva

    (Cellectis, Inc.)

  • Brian W. Busser

    (Cellectis, Inc.)

  • Sonal Temburni

    (Cellectis, Inc.)

  • Billal Jahangiri

    (Cellectis, Inc.)

  • Anne-Sophie Gautron

    (Cellectis)

  • Alan Maréchal

    (Cellectis)

  • Alexandre Juillerat

    (Cellectis, Inc.)

  • Alan Williams

    (Cellectis, Inc.)

  • Stéphane Depil

    (Cellectis)

  • Philippe Duchateau

    (Cellectis)

  • Laurent Poirot

    (Cellectis)

  • Julien Valton

    (Cellectis, Inc.)

Abstract

Endowing chimeric antigen receptor (CAR) T cells with additional potent functionalities holds strong potential for improving their antitumor activity. However, because potency could be deleterious without control, these additional features need to be tightly regulated. Immune pathways offer a wide array of tightly regulated genes that can be repurposed to express potent functionalities in a highly controlled manner. Here, we explore this concept by repurposing TCR, CD25 and PD1, three major players of the T cell activation pathway. We insert the CAR into the TCRα gene (TRACCAR), and IL-12P70 into either IL2Rα or PDCD1 genes. This process results in transient, antigen concentration-dependent IL-12P70 secretion, increases TRACCAR T cell cytotoxicity and extends survival of tumor-bearing mice. This gene network repurposing strategy can be extended to other cellular pathways, thus paving the way for generating smart CAR T cells able to integrate biological inputs and to translate them into therapeutic outputs in a highly regulated manner.

Suggested Citation

  • Mohit Sachdeva & Brian W. Busser & Sonal Temburni & Billal Jahangiri & Anne-Sophie Gautron & Alan Maréchal & Alexandre Juillerat & Alan Williams & Stéphane Depil & Philippe Duchateau & Laurent Poirot , 2019. "Repurposing endogenous immune pathways to tailor and control chimeric antigen receptor T cell functionality," Nature Communications, Nature, vol. 10(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13088-3
    DOI: 10.1038/s41467-019-13088-3
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    Cited by:

    1. Irene Andreu-Saumell & Alba Rodriguez-Garcia & Vanessa Mühlgrabner & Marta Gimenez-Alejandre & Berta Marzal & Joan Castellsagué & Fara Brasó-Maristany & Hugo Calderon & Laura Angelats & Salut Colell &, 2024. "CAR affinity modulates the sensitivity of CAR-T cells to PD-1/PD-L1-mediated inhibition," Nature Communications, Nature, vol. 15(1), pages 1-18, December.
    2. Arianna Moiani & Gil Letort & Sabrina Lizot & Anne Chalumeau & Chloe Foray & Tristan Felix & Diane Clerre & Sonal Temburni-Blake & Patrick Hong & Sophie Leduc & Noemie Pinard & Alan Marechal & Eduardo, 2024. "Non-viral DNA delivery and TALEN editing correct the sickle cell mutation in hematopoietic stem cells," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    3. Sumin Jo & Shipra Das & Alan Williams & Anne-Sophie Chretien & Thomas Pagliardini & Aude Roy & Jorge Postigo Fernandez & Diane Clerre & Billal Jahangiri & Isabelle Chion-Sotinel & Sandra Rozlan & Emil, 2022. "Endowing universal CAR T-cell with immune-evasive properties using TALEN-gene editing," Nature Communications, Nature, vol. 13(1), pages 1-16, December.

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