Martin Oft
Engineering IL-2 to increase anti-tumor efficacy and mitigate capillary leak
High-dose Interleukin-2 (IL-2) monotherapy induces complete responses in cancer patients, but severe acute vascular toxicities limit its application1,2. IL-2 broadly activates all lymphocytes including NK-cells by binding the intermediate-affinity, dimeric IL-2Rβ/γ (CD122/CD132). Upregulation of IL-2Rα on antigen activated T-cells and regulatory T-cells (Treg) leads to the formation of the high-affinity, trimeric IL-2 receptor, IL-2Rα/β/γ (CD25/CD122/CD132) increasing the sensitivity to IL-23. To reduce Treg selectivity, IL-2 variants with reduced CD25-binding (non-α-IL-2) have been studied4, but demonstrate significant toxicities and limited monotherapy efficacy in clinical trials5,6. To avoid this toxicity and deliver IL-2 to tumor specific T cells we develop highly selective IL-2 variants, targeting tumor reactive T cells.
Our novel α/β-biased IL-2s bind selectively to the highly upregulated IL-2Rα/β/γ on antigen activated T-cells resulting in improved efficacy while avoiding vascular toxicity. In contrast, wt-IL-2 and non-α-IL-2 broadly activated all lymphocytes leading to systemic tissue inflammation, pulmonary inflammation and capillary leak syndrome. In contrast, α/β-IL-2s avoided broad systemic lymphocyte activation but resulted in increased intratumoral, tumor specific CD25+PD-1+CD28+CD8+ T cells, eliciting monotherapy complete responses and tumor immune memory. Systemically increased Tregs did not interfere with anti-tumor efficacy, as intratumoral Tregs were inhibited, improving the intratumoral CD8 to Treg ratio.
Our orthogonal IL-2 – IL-2Rb system enables the specific activation of adoptively transferred T cells expressing the human orthogonal IL-2Rb (hoRb). Orthogonal IL-2 (STK-009) does not activate the endogenous IL-2 receptor. As a consequence, adoptively transferred T cells can be expanded in mice for many months, with the persistence of both stem cell memory (TSCM) and effector T cells (TEMRA). The combination of STK-009 with orthogonal CD19-directed CAR T cells (SYNCAR-001) lead to the elimination of bulky B cell lymphoma in mice. Similarly, STK-009 enables orthogonal GPC3-directed CAR T cells (SYNCAR-002) to eliminate large hepatocellular cancers. In addition, orthogonal IL-2 system allows adoptive transfer and expansion of T cells in syngeneic hosts without lymphodepletion of the host.
In summary, IL-2 variants, specifically directed toward the tumor reactive T cell population can unleash the power of IL-2 without the vascular toxicity observed with high dose IL-2 treatment.
1 Atkins, M. B. et al. High-dose recombinant interleukin 2 therapy for patients with metastatic melanoma: analysis of 270 patients treated between 1985 and 1993. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 17, 2105-2116 (1999). https://doi.org:10.1200/JCO.1999.17.7.2105
2 Dutcher, J. P. et al. High dose interleukin-2 (Aldesleukin) - expert consensus on best management practices-2014. Journal for immunotherapy of cancer 2, 26 (2014). https://doi.org:10.1186/s40425-014-0026-0
3 Liao, W., Lin, J. X. & Leonard, W. J. Interleukin-2 at the crossroads of effector responses, tolerance, and immunotherapy. Immunity 38, 13-25 (2013). https://doi.org:10.1016/j.immuni.2013.01.004
4 Levin, A. M. et al. Exploiting a natural conformational switch to engineer an interleukin-2 'superkine'. Nature 484, 529-533 (2012). https://doi.org:10.1038/nature10975
5 Diab, A. et al. Bempegaldesleukin (NKTR-214) plus Nivolumab in Patients with Advanced Solid Tumors: Phase I Dose-Escalation Study of Safety, Efficacy, and Immune Activation (PIVOT-02). Cancer Discov 10, 1158-1173 (2020). https://doi.org:10.1158/2159-8290.CD-19-1510
6 Janku, F. et al. Abstract LB041: THOR-707 (SAR444245), a novel not-alpha IL-2 as monotherapy and in combination with pembrolizumab in advanced/metastatic solid tumors: Interim results from HAMMER, an open-label, multicenter phase 1/2 Study. Cancer research 81 (2021).