{
  "abstract": "Background Interleukin-2 (IL-2) that stimulates T cell activation has renewed interest as a target for cancer immunotherapy. However, its clinical efficacy is still limited without appropriate patient stratification. HM16390 is an IL-2 analog engineered with enhanced IL-2Rβ binding and fine-tuned IL-2Rα affinity. This study aimed to identify transcriptomic biomarkers predictive of therapeutic response to HM16390 in cancer patients, using comprehensive datasets from patients previously treated with immune checkpoint inhibitors (ICIs).Methods We analyzed bulk RNA-seq data from pre- and post-treatment blood (n=531) and pre-treatment tumor tissues (n=4,068) across nine cancer types, alongside single-cell RNA-seq data from blood (n=256, five types) and tumors (n=342, eight types). Using Cox proportional hazards models, we assessed associations between gene expression, including IL-2-related and immune checkpoint genes and treatment response. IL-2 pathway activity was quantified via single-sample gene set enrichment analysis using the MSigDB Hallmark ‘IL-2/STAT5 signaling’ set and evaluated for ICI response. Stem-like and exhausted T cell signatures from single-cell data were examined in relation to ICI efficacy. Multivariate models incorporating pre- and post-treatment transcriptomic profiles were used to validate candidate biomarkers.Results Interleukin-2 receptor alpha (IL-2Rα) expression in both blood and tumors was significantly associated with improved ICI response and survival benefit, demonstrated by increased odds ratios (OR: blood 2.33; tumor 1.09) and reduced hazard ratios (HR: blood 0.52; tumor 0.89). IL-2 pathway activity inferred from tumor bulk RNA-seq via BIOCARTA, MSigDB, PID, and REACTOME also showed a significant positive association with clinical response with higher ORs. T cell signatures reflecting stem-like and exhausted phenotypes (Tex) were similarly associated with favorable outcomes, indicating higher ORs (stem-like T in blood/tumor 2.02/1.15; Tex in blood/tumor 1.67/1.28) and lower HRs (stem-like T in blood/tumor 0.48/0.84; Tex in blood/tumor 0.61/0.79). Multivariate analysis identified baseline IL-2Rα expression and post-treatment stem-like T cell enrichment in blood, along with tumor PD-1, as independent predictors of ICI response.Conclusions IL-2Rα (CD25) expression and stem-like T cell signatures were identified as transcriptomic biomarkers predictive of therapeutic response to IL-2-based immunotherapy. Interestingly, both markers reflect the critical role of IL-2 binding to the CD25 receptor on T cells, these findings suggest the importance of CD25 engagement in immunotherapy. Their clinical utility will be further evaluated in a clinical trial of HM16390, whose defining feature is its optimal affinity for IL2Rα, along with a strong enhancement in IL-2Rβ binding.",
  "authors": [
    {
      "affiliations": [
        "Hanmi Pharm. Co., Ltd, Hwaseong-si, Republic of Korea"
      ],
      "name": "Yu-Yon Kim"
    },
    {
      "affiliations": [
        "Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea"
      ],
      "name": "Jinhyeon An"
    },
    {
      "affiliations": [
        "Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea"
      ],
      "name": "Junho Kang"
    },
    {
      "affiliations": [
        "Hanmi Pharm. Co., Ltd, Hwaseong-si, Republic of Korea"
      ],
      "name": "Hosun Lee"
    },
    {
      "affiliations": [
        "Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea"
      ],
      "name": "Jae Soon Park"
    },
    {
      "affiliations": [
        "Hanmi Pharm. Co., Ltd, Hwaseong-si, Republic of Korea"
      ],
      "name": "Jaehyuk Choi"
    },
    {
      "affiliations": [
        "Hanmi Pharm. Co., Ltd, Hwaseong-si, Republic of Korea"
      ],
      "name": "Jinyoung Kim"
    },
    {
      "affiliations": [
        "Hanmi Pharm. Co., Ltd, Hwaseong-si, Republic of Korea"
      ],
      "name": "Daejin Kim"
    },
    {
      "affiliations": [
        "Hanmi Pharm. Co., Ltd, Hwaseong-si, Republic of Korea"
      ],
      "name": "Haemin Chon"
    },
    {
      "affiliations": [
        "Hanmi Pharm. Co., Ltd, Hwaseong-si, Republic of Korea"
      ],
      "name": "In Young Choi"
    },
    {
      "affiliations": [
        "Korea Advanced Institute of Science and Technology, Daejeon, Republic of Korea"
      ],
      "name": "Jung Kyoon Choi"
    }
  ],
  "title": "137 Identifying predictive biomarkers for HM16390, a novel long-acting IL-2 analog, by analyzing single-cell and bulk transcriptomic data of immune checkpoint inhibitors treated patients",
  "uid": "d9c43e33-4234-58a7-abf6-4a5c0fc8b6dc"
}