Frontiers in Immunology (Jul 2022)

PD-1 Inhibitor Combined With Radiotherapy and GM-CSF (PRaG) in Patients With Metastatic Solid Tumors: An Open-Label Phase II Study

  • Yuehong Kong,
  • Yuehong Kong,
  • Yuehong Kong,
  • Xiangrong Zhao,
  • Xiangrong Zhao,
  • Xiangrong Zhao,
  • Meiling Xu,
  • Meiling Xu,
  • Meiling Xu,
  • Jie Pan,
  • Yifu Ma,
  • Yifu Ma,
  • Yifu Ma,
  • Li Zou,
  • Li Zou,
  • Li Zou,
  • Qiliang Peng,
  • Qiliang Peng,
  • Qiliang Peng,
  • Junjun Zhang,
  • Junjun Zhang,
  • Junjun Zhang,
  • Cunjin Su,
  • Zhi Xu,
  • Wei Zhou,
  • Wei Zhou,
  • Wei Zhou,
  • Yong Peng,
  • Yong Peng,
  • Yong Peng,
  • Jiabao Yang,
  • Jiabao Yang,
  • Jiabao Yang,
  • Chengliang Zhou,
  • Chengliang Zhou,
  • Chengliang Zhou,
  • Yujia Li,
  • Yujia Li,
  • Yujia Li,
  • Qiuchen Guo,
  • Guangqiang Chen,
  • Hongya Wu,
  • Hongya Wu,
  • Pengfei Xing,
  • Pengfei Xing,
  • Pengfei Xing,
  • Liyuan Zhang,
  • Liyuan Zhang,
  • Liyuan Zhang

DOI
https://doi.org/10.3389/fimmu.2022.952066
Journal volume & issue
Vol. 13

Abstract

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Patients with metastatic cancer refractory to standard systemic therapies have a poor prognosis and few therapeutic options. Radiotherapy can shape the tumor microenvironment (TME) by inducing immunogenic cell death and promoting tumor recognition by natural killer cells and T lymphocytes. Granulocyte macrophage-colony stimulating factor (GM-CSF) was known to promote dendric cell maturation and function, and might also induce the macrophage polarization with anti-tumor capabilities. A phase II trial (ChiCTR1900026175) was conducted to assess the clinical efficacy and safety of radiotherapy, PD-1 inhibitor and GM-CSF (PRaG regimen). This trial was registered at http://www.chictr.org.cn/index.aspx. A PRaG cycle consisted of 3 fractions of 5 or 8 Gy delivered for one metastatic lesion from day 1, followed by 200 μg subcutaneous injection of GM-CSF once daily for 2 weeks, and intravenous infusion of PD-1 inhibitor once within one week after completion of radiotherapy. The PRaG regimen was repeated every 21 days for at least two cycles. Once the PRaG therapy was completed, the patient continued PD-1 inhibitor monotherapy until confirmed disease progression or unacceptable toxicity. The primary endpoint was objective response rate (ORR). A total of 54 patients were enrolled with a median follow-up time of 16.4 months. The ORR was 16.7%, and the disease control rate was 46.3% in intent-to-treat patients. Median progression-free survival was 4.0 months (95% confidence interval [CI], 3.3 to 4.8), and median overall survival was 10.5 months (95% CI, 8.7 to 12.2). Grade 3 treatment-related adverse events occurred in five patients (10.0%) and grade 4 in one patient (2.0%). Therefore, the PRaG regimen was well tolerated with acceptable toxicity and may represent a promising salvage treatment for patients with chemotherapy-refractory solid tumors. It is likely that PRaG acts via heating upthe TME with radiotherapy and GM-CSF, which was further boosted by PD-1 inhibitors.

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