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Background <p>The low response rate of anti-PD-1 monoclonal antibodies (mAbs) in hepatocellular carcinoma (HCC) requires the development of combination immunotherapy strategies to improve their efficacy. This study aimed to use LAG-3-targeted PET imaging to monitor the efficacy of anti-PD-1 mAb, a stimulator of interferon genes (STING) agonist, and anti-LAG-3 mAb, both individually and in combination. Furthermore, we evaluated the potential of a triple immunotherapy regimen (anti-PD-1 mAb, STING agonist, and anti-LAG-3 mAb) to improve HCC treatment.</p> Methods <p>The LAG-3 inhibitor C25 based on a cyclic peptide was chelated with NOTA, radiolabeled with [<sup>68</sup>Ga]GaCl<sub>3</sub>. The resulting [<sup>68</sup>Ga]Ga-NOTA-C25 underwent in vivo PET imaging and ex vivo biodistribution examination in Hepa1-6 tumor-bearing mice. [<sup>68</sup>Ga]Ga-NOTA-C25 PET was used to monitor the efficacy of monotherapy and dual immunotherapy with anti-PD-1 monoclonal antibody (mAb) and STING agonists. The tumor uptake of [<sup>68</sup>Ga]Ga-NOTA-C25, tumor response, and survival rates were measured following different treatments. The therapeutic efficacy, molecular mechanisms, and safety of triple immunotherapy were validated using histopathological analysis and flow cytometry.</p> Results <p>[<sup>68</sup>Ga]Ga-NOTA-C25 PET imaging effectively and noninvasively detected LAG-3<sup>+</sup> tumor-infiltrating lymphocytes (TILs) in Hepa1-6 tumor-bearing mice. In mice treated with anti-PD-1 mAb, STING agonist, or a combination immunotherapy, [<sup>68</sup>Ga]Ga-NOTA-C25 PET revealed significantly increased LAG-3<sup>+</sup> TIL levels. At the treatment endpoint, the combination of the STING agonist with the anti-PD-1 mAb resulted in a significantly higher uptake (1.35 ± 0.191%ID/g) compared to the control group (0.402 ± 0.017%ID/g), the anti-PD-1 mAb group (0.647 ± 0.037%ID/g), and the STING agonist group (0.874 ± 0.089%ID/g). Uptake of [<sup>68</sup>Ga]Ga-NOTA-C25 was positively correlated with tumor therapeutic effects and survival rates. Triple immunotherapy with anti-PD-1 mAb, a STING agonist, and anti-LAG-3 mAb further enhanced efficacy compared to any dual immunotherapy regimen, and treatment efficacy was linearly associated with [<sup>68</sup>Ga]Ga-NOTA-C25 tumor uptake.</p> Conclusions <p>Anti-PD-1 mAb and STING agonists have shown notable synergy in upregulating LAG-3 expression on TILs in HCC, which can be successfully tracked by [<sup>68</sup>Ga]Ga-NOTA-C25 PET imaging. Furthermore, integration of a triple immunotherapy regimen comprising an anti-PD-1 mAb, STING agonist, and anti-LAG-3 mAb demonstrated a significant improvement in therapeutic efficacy over dual immunotherapy approaches.</p>

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Combination immunotherapy targeting LAG-3, PD-1 and STING suppresses hepatocellular carcinoma as monitored by LAG-3 targeted PET imaging

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月12日

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  • Zhen Quan,
  • Yu Gao,
  • Bo Sun,
  • Yiwan Guo,
  • Ziwei Jin,
  • Na Hao,
  • Dawei Jiang,
  • Chuansheng Zheng,
  • Xin Li,
  • Quan Chen

摘要

Background

The low response rate of anti-PD-1 monoclonal antibodies (mAbs) in hepatocellular carcinoma (HCC) requires the development of combination immunotherapy strategies to improve their efficacy. This study aimed to use LAG-3-targeted PET imaging to monitor the efficacy of anti-PD-1 mAb, a stimulator of interferon genes (STING) agonist, and anti-LAG-3 mAb, both individually and in combination. Furthermore, we evaluated the potential of a triple immunotherapy regimen (anti-PD-1 mAb, STING agonist, and anti-LAG-3 mAb) to improve HCC treatment.

Methods

The LAG-3 inhibitor C25 based on a cyclic peptide was chelated with NOTA, radiolabeled with [68Ga]GaCl3. The resulting [68Ga]Ga-NOTA-C25 underwent in vivo PET imaging and ex vivo biodistribution examination in Hepa1-6 tumor-bearing mice. [68Ga]Ga-NOTA-C25 PET was used to monitor the efficacy of monotherapy and dual immunotherapy with anti-PD-1 monoclonal antibody (mAb) and STING agonists. The tumor uptake of [68Ga]Ga-NOTA-C25, tumor response, and survival rates were measured following different treatments. The therapeutic efficacy, molecular mechanisms, and safety of triple immunotherapy were validated using histopathological analysis and flow cytometry.

Results

[68Ga]Ga-NOTA-C25 PET imaging effectively and noninvasively detected LAG-3+ tumor-infiltrating lymphocytes (TILs) in Hepa1-6 tumor-bearing mice. In mice treated with anti-PD-1 mAb, STING agonist, or a combination immunotherapy, [68Ga]Ga-NOTA-C25 PET revealed significantly increased LAG-3+ TIL levels. At the treatment endpoint, the combination of the STING agonist with the anti-PD-1 mAb resulted in a significantly higher uptake (1.35 ± 0.191%ID/g) compared to the control group (0.402 ± 0.017%ID/g), the anti-PD-1 mAb group (0.647 ± 0.037%ID/g), and the STING agonist group (0.874 ± 0.089%ID/g). Uptake of [68Ga]Ga-NOTA-C25 was positively correlated with tumor therapeutic effects and survival rates. Triple immunotherapy with anti-PD-1 mAb, a STING agonist, and anti-LAG-3 mAb further enhanced efficacy compared to any dual immunotherapy regimen, and treatment efficacy was linearly associated with [68Ga]Ga-NOTA-C25 tumor uptake.

Conclusions

Anti-PD-1 mAb and STING agonists have shown notable synergy in upregulating LAG-3 expression on TILs in HCC, which can be successfully tracked by [68Ga]Ga-NOTA-C25 PET imaging. Furthermore, integration of a triple immunotherapy regimen comprising an anti-PD-1 mAb, STING agonist, and anti-LAG-3 mAb demonstrated a significant improvement in therapeutic efficacy over dual immunotherapy approaches.