Thymosin alpha-1–enhanced PRaG regimen: A novel approach to boosting immune dynamics and therapeutic efficacy in advanced solid tumors.

Abstract

e14606 Background: Severe lymphopenia remains a significant obstacle to the long-term success of immunotherapy. In combination therapies, radiation-induced lymphopenia further impairs the immune response, substantially limiting therapeutic outcomes. The PRaG regimen-comprising programmed cell death protein 1 (PD-1) inhibitors, radiotherapy, and granulocyte-macrophage colony-stimulating factor (GM-CSF)-has demonstrated clinical efficacy in patients with metastatic or refractory solid tumors who have failed systemic treatments. Thymosin Alpha 1 (Tα-1), a well-established immunomodulator, is known to protect lymphocytes, reduce lymphocytopenia during radiotherapy, and enhance T lymphocytes. This study aims to evaluate the enhanced efficacy and safety of a novel Tα-1-based PRaG regimen in patients with advanced/refractory solid tumors, with a focus on uncovering the underlying mechanisms influencing T cell dynamics. Methods: Patients with advanced solid tumors who had progressed after prior systemic therapy were stratified according to baseline T lymphocyte counts and received personalized Tα-1 dosing. Patients with low T lymphocyte counts received a 7-day loading dose, while those with higher counts received maintenance Tα-1 (1.6 mg, thrice weekly) in combination with the PRaG regimen for at least two cycles. Following PRaG treatment, patients continued PD-1 inhibitors and Tα-1 until disease progression or intolerable adverse events. The primary endpoint was the objective response rate (ORR), assessed by RECIST 1.1 criteria. Peripheral immune profiling was conducted using flow cytometry (FACS), single-cell sequencing, and TCR sequencing. Results: Among 21 enrolled patients, the ORR was 23.8% and the disease control rate (DCR) was 47.6%. The median progression-free survival (PFS) was 3.97 months (95% CI: 2.67–6.97 months),, with no Grade 3 or above adverse events reported. Immune analysis revealed significant increases in CD8+ T cells, NK cells, and CD4 + T EM cells post-Tα-1 loading, with a notable decrease in Tregs (p = 0.001). Single-cell sequencing demonstrated higher clonality in GZMK-CD8 + T and LEF1-Naïve CD8 + T cells in responders, while TRDV2-CD8 + T cells expanded in non-responders. Conclusions: The integration of Tα-1 into the PRaG regimen represents a significant innovation, offering enhanced efficacy and a favorable safety profile. Detailed immune profiling uncovered distinct T cell dynamics associated with treatment response, highlighting potential biomarkers for future clinical applications. Further validation in larger cohorts is warranted. Clinical trial information: NCT05790447 .