Adoptive cell therapy using T cell receptors equipped with ICOS yields durable anti-tumor response

  1. Alexandre Marraffa
  2. Cor Berrevoets
  3. Margherita Mosiello
  4. Rebecca Wijers
  5. Daphne Roelofs
  6. Mandy van Brakel
  7. Kim Kroese
  8. Marlies J.W. Peeters
  9. Willem A. Dik
  10. Andre Kunert
  11. Rachel J.M. Abbott
  12. Dora Hammerl
  13. Christopher Schliehe
  14. Reno Debets
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Abstract

Treatment with adoptively transferred T cells is challenged by limited longevity of therapeutic cells within tumors. To enhance the durability of anti-tumor T cell products, we have created T cell receptors (TCRs) with built-in co-stimulatory molecules. We observed that TCRs coupled to ICOS mediated exceptionally long-term responses including delay of tumor recurrence and cures in a mouse tumor model. TCR:ICOS T cells showed enhanced and antigen-specific production of inflammatory cytokines and resistance to exhaustion. Genetic ablation of ICOS-mediated activation of the PI3K-NFκB pathway neutralized the long-term anti-tumor effects. To translate TCR:ICOS to human T cells, we identified a single amino acid change in the cytosolic tail which was necessary for functional surface expression. Notably, the optimized receptor sustained performance of human T cells upon repeated stimulation across multiple antigen specificities. Collectively, we present a novel and uniformly applicable TCR:ICOS format that supports fitter T cell products for adoptive cell therapy.

Highlights

Newly designed co-stimulatory TCR, with extracellular TCR-V and C domains coupled to CD28 transmembrane domain, and ICOS and CD3ε intracellular domains (in short TCR:ICOS) provides:

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    durable anti-tumor response and T cell persistence in mouse model

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    inflammatory T cell phenotype and resistance to T cell exhaustion

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    effects via PI3K and NFκB activation

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    translation to human T cells upon single amino acid mutation in TCR:ICOS tail

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    extension to multiple clinically relevant TCRs while preserving prolonged T cell fitness

Abstract Figure

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