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

Giulia Parisi, Justin D. Saco, Felix B. Salazar, Jennifer Tsoi, Paige Krystofinski, Cristina Puig-Saus, Ruixue Zhang, Jing Zhou, Gardenia C. Cheung-Lau, Alejandro J. Garcia, Catherine S. Grasso, Richard Tavaré, Siwen Hu-Lieskovan, Sean Mackay, Jonathan Zalevsky, Chantale Bernatchez, Adi Diab, Anna M. Wu, Begoña Comin-Anduix, Deborah Charych and Antoni Ribas ()
Additional contact information
Giulia Parisi: David Geffen School of Medicine at UCLA
Justin D. Saco: David Geffen School of Medicine at UCLA
Felix B. Salazar: David Geffen School of Medicine at UCLA
Jennifer Tsoi: David Geffen School of Medicine at UCLA
Paige Krystofinski: David Geffen School of Medicine at UCLA
Cristina Puig-Saus: David Geffen School of Medicine at UCLA
Ruixue Zhang: David Geffen School of Medicine at UCLA
Jing Zhou: Isoplexis Corporation
Gardenia C. Cheung-Lau: David Geffen School of Medicine at UCLA
Alejandro J. Garcia: David Geffen School of Medicine at UCLA
Catherine S. Grasso: David Geffen School of Medicine at UCLA
Richard Tavaré: Regeneron Pharmaceuticals, Inc.
Siwen Hu-Lieskovan: David Geffen School of Medicine at UCLA
Sean Mackay: Isoplexis Corporation
Jonathan Zalevsky: Nektar Therapeutics
Chantale Bernatchez: University of Texas MD Anderson Cancer Center
Adi Diab: University of Texas MD Anderson Cancer Center
Anna M. Wu: David Geffen School of Medicine at UCLA
Begoña Comin-Anduix: David Geffen School of Medicine at UCLA
Deborah Charych: Nektar Therapeutics
Antoni Ribas: David Geffen School of Medicine at UCLA

Nature Communications, 2020, vol. 11, issue 1, 1-12

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-12901-3

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