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

Abstract

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.

Anti-PD-1 immunotherapy combined with stereotactic body radiation therapy and GM-CSF for the treatment of advanced malignant PEComa: A case report

“…The role of PD-1 inhibitors and radiation therapy in the treatment regimen of PEComa deserves further investigation. Recently, triple therapy with the PD-1 inhibitor and SBRT has been shown be safe and may be used as a salvage therapy for refractory tumours (14,16). In this case, we used the triple combination of a PD-1 inhibitor, GM-CSF and SBRT to treat PEComa and obtained a good curative effect.…”

“…Studies have shown that multisite stereotactic body radiotherapy (SBRT) combined with PD-1 inhibitors may achieve better clinical outcomes ( 12 , 13 ). The triple use of PD-1 inhibitors, GM-CSF and SBRT may be more likely to produce abscopal effects ( 14 , 15 ).…”

Granulocyte Apheresis: Can It Be Associated with Anti PD-1 Therapy for Melanoma?

“…This informative association constitutes the basis for expanding our knowledge on the role of neutrophils in cancer immunology and for discovering neutrophil-targeted immunotherapies [ 5 ]. Specific neutrophil subtypes within the TME play a key role in shifting the cancer-immune set point from an anti-tumor to a pro-tumor phenotype [ 27 ]; novel approaches targeting cancer-associated neutrophils may be devised to reshape TME-promoting tumor recognition by T lymphocytes and natural killer cells [ 4 ].…”

“…Effective approaches may be further narrowed in cases of elevated cancer burden and of multiple secondary localizations of malignancy. These limitations created an urgent need to investigate novel approaches to target additional specific components of the cancer–immunity cycle, which may heat up the tumor microenvironment (TME) promoting cancer cell recognition and boosting the effect of PD-1 inhibitors [ 5 ].…”

Implications of the Organ-Specific Immune Environment for Immune Priming Effect of Radiotherapy in Metastatic Setting

“…Only indirect indications can be extracted from immunoradiation trials. However, in most cases, these studies evaluated a small number of patients, and no strong evidence can be drawn (see Table 1 ) [ 90 , 118 , 119 , 120 , 121 , 122 , 123 , 124 , 125 , 126 , 127 ].…”