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.
Highlights
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
The anti-tumor effects of NKTR-214 to support the expansion and functionality of adoptively transferred antitumor T cells was evaluated in mice bearing established B16-F10 murine melanoma tumors larger than 150 mm[3] at the time of ACT
The adoptively transferred cells were only administered on day 1 after lymphodepletion, and ACT was not repeated with subsequent administrations of either NKTR-214 or IL-2
Summary
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. Clinical protocols of ACT infusing ex vivo expanded tumor-infiltrating lymphocytes (TIL) or T cell receptor (TCR) engineered peripheral blood T cells require the concomitant administration of interleukin 2 (IL-2, aldesleukin), usually administered intravenously at the highest tolerated dose every 8 h in an inpatient hospital setting to support expansion and function of the adoptively transferred cells[2]. This dosing regimen results in a high peak of exposure explaining the acute toxicities, which is of very short duration and suboptimally activates the IL-2 receptor[3]. We analyze the T cell polyfunctionality of murine T cells and explore the polyfunctionality of human T cells obtained from patients treated with NKTR-214 within a single agent, phase I clinical trial
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