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Persistence of adoptively transferred T cells with a kinetically engineered IL-2 receptor agonist.

  • Author(s): Parisi, Giulia;
  • Saco, Justin D;
  • Salazar, Felix B;
  • Tsoi, Jennifer;
  • Krystofinski, Paige;
  • Puig-Saus, Cristina;
  • Zhang, Ruixue;
  • Zhou, Jing;
  • Cheung-Lau, Gardenia C;
  • Garcia, Alejandro J;
  • Grasso, Catherine S;
  • Tavaré, Richard;
  • Hu-Lieskovan, Siwen;
  • Mackay, Sean;
  • Zalevsky, Jonathan;
  • Bernatchez, Chantale;
  • Diab, Adi;
  • Wu, Anna M;
  • Comin-Anduix, Begoña;
  • Charych, Deborah;
  • Ribas, Antoni
  • et al.

Interleukin-2 (IL-2) is a component of most protocols of adoptive cell transfer (ACT) therapy for cancer, but is limited by short exposure and high toxicities. NKTR-214 is a kinetically-engineered IL-2 receptor βγ (IL-2Rβγ)-biased agonist consisting of IL-2 conjugated to multiple releasable polyethylene glycol chains resulting in sustained signaling through IL-2Rβγ. We report that ACT supported by NKTR-214 increases the proliferation, homing and persistence of anti-tumor T cells compared to ACT with IL-2, resulting in superior antitumor activity in a B16-F10 murine melanoma model. The use of NKTR-214 increases the number of polyfunctional T cells in murine spleens and tumors compared to IL-2, and enhances the polyfunctionality of T and NK cells in the peripheral blood of patients receiving NKTR-214 in a phase 1 trial. In conclusion, NKTR-214 may have the potential to improve the antitumor activity of ACT in humans through increased in vivo expansion and polyfunctionality of the adoptively transferred T cells.

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