Authors: Zhu Zhengfei et al. Fudan University Shanghai Cancer Center Translated by: Kong Yuehong Reviewed by: Zhang Liyuan PRaG Treatment Center, The Second Affiliated Hospital of Soochow University
Advanced driver gene-negative non-small cell lung cancer (NSCLC) refers to lung cancer patients without common oncogenic driver mutations (such as EGFR, ALK, etc.). These patients typically do not benefit from targeted therapy, and treatment options are mainly focused on chemotherapy, immunotherapy, and radiotherapy. In recent years, immune checkpoint inhibitors (ICIs), especially antibodies targeting PD-1 and PD-L1, have become important treatment modalities for advanced NSCLC. However, despite the significant effects of immunotherapy in improving overall survival (OS) and progression-free survival (PFS) in patients with advanced NSCLC, challenges of primary and acquired resistance still exist. Therefore, many studies have attempted to enhance efficacy by combining immunotherapy with other therapies.
In August 2024, an article published in Nature Communications titled “Sintilimab in combination with stereotactic body radiotherapy and granulocyte-macrophage colony-stimulating factor in metastatic non-small cell lung cancer: The multicenter SWORD phase 2 trial” reported an innovative treatment strategy [1]. This study explored the efficacy of a triplet therapy consisting of a PD-1 antibody (sintilimab), stereotactic body radiotherapy, and an immunomodulator (GM-CSF) for advanced driver gene-negative non-small cell lung cancer. This study provides new evidence and perspectives for radio-immunotherapy combination therapy, finding that the triplet therapy can significantly improve the objective response rate and patient survival without increasing serious side effects. The SWORD study is like a sharp sword, symbolizing precise decision-making and accurate strikes against tumors. Just as the therapy in the study aims to strengthen the patient’s immune response and combat advanced non-small cell lung cancer through precise radiotherapy and immune modulation.
Study Design and Therapeutic Efficacy
This is a national multicenter, single-arm, phase II clinical trial that enrolled 51 patients with advanced driver gene-negative non-small cell lung cancer who had failed first-line platinum-doublet chemotherapy. The study was designed to evaluate the efficacy and safety of the triplet therapy of sintilimab, stereotactic body radiotherapy, and GM-CSF. The primary endpoint was objective response rate (ORR), and secondary endpoints were progression-free survival (PFS), overall survival (OS), abscopal response rate (ASR), and treatment-related adverse events (TRAEs). The median follow-up time of this study was 32.1 months. Among 49 evaluable patients, 18 patients (36.7%, 90% CI 25.3%-49.5%) achieved partial response (PR), reaching the primary endpoint of this study. The median PFS was 5.9 months (95% CI 2.5–9.3 months), and the median OS was 18.4 months (95% CI 9.7–27.1 months). The ASR was 30.6% (95% CI 18.3%–45.4%).
Figure 1: Analysis of objective response rate and survival follow-up data in 49 evaluable patients.
Safety Assessment
In terms of safety, although the vast majority of patients (86.3%) experienced TRAEs, only 6 patients (11.8%) experienced grade 3 TRAEs, and no grade 4-5 serious adverse reactions were observed. Compared to immunotherapy alone, there was no significant increase in toxic side effects.
Figure 2: Changes in immune cells in the tumor microenvironment of unirradiated lesions before and after SBRT.
Efficacy Comparison and Analysis with Other Studies
Compared with previous studies of single-agent PD-1 inhibitor therapy (e.g., the ORIENT-3 study, where sintilimab’s ORR was 20%), the triplet therapy’s ORR of 36.7% showed a significant improvement in efficacy. The efficacy is comparable to dual therapy of radiotherapy combined with PD-1 inhibitors, such as the PEMBRO-RT study, where pembrolizumab combined with radiotherapy had an ORR of 36.0%, which is close to the results of this study. In comparison, the survival data of the SWORD study shows strong potential advantages, especially in patients with high tumor burden, achieving better treatment outcomes, which is of important clinical significance for the treatment of advanced non-small cell lung cancer. However, the role of GM-CSF in combination therapy still needs further exploration. GM-CSF has been shown to promote the maturation of antigen-presenting cells and enhance radiotherapy-induced anti-tumor immune responses. In the SWORD study, the triplet therapy including GM-CSF, sintilimab, and SBRT not only reached the primary endpoint of the study, but also the patients in the study had a high tumor burden, with 90.2% of patients having >5 metastatic lesions and 72.5% of patients having more than 3 metastatic organs at enrollment. Therefore, GM-CSF may have played a potential role in this context.
Biomarker Exploration
This article also collected pre- and post-treatment blood samples and puncture samples of unirradiated lesions before and after radiotherapy for biomarker exploration, which provides important clues for future treatment optimization and personalized strategy development. The study specifically pointed out the key role of follicular helper T cells (Tfh) and the IL-21 signaling pathway in the systemic anti-tumor immune response triggered by SBRT.
- Potential Link between Tfh Cells and Radio-Immunotherapy Efficacy
Tfh cells are an important subset of CD4+ T cells, responsible for regulating B cell activation and antibody production. Past studies have shown that Tfh cells can promote anti-tumor immune responses by secreting IL-21. This article for the first time clearly demonstrated that SBRT can significantly increase the proportion of Tfh cells in unirradiated tumor lesions and peripheral blood, as well as the level of IL-21 in peripheral blood. Furthermore, patients with high Tfh levels after treatment were positively correlated with patient prognosis. This finding indicates that SBRT not only has a direct killing effect on local tumors, but may also trigger a strong systemic immune response through Tfh cells.
Figure 3: Changes in circulating Tfh and CD49a+Tfh cells before and after treatment and their correlation with prognosis.
- CD49a+Tfh Cells and Survival Prognosis Analysis
More interestingly, the study also discovered a special subtype of CD49a+Tfh cells, which may play an important role in the immune response triggered by SBRT. CD49a is a molecule associated with T cell activation and directional migration, and its increased expression is associated with better prognosis. Although these results need further research to verify, CD49a+Tfh cells may be an important target for regulating anti-tumor immune responses in future radio-immunotherapy.
- Role of IL-21 and Other Immune Factors in Anti-Tumor Immunity
IL-21, as an important cytokine secreted by Tfh cells, is not only proven in this article to have a positive impact on the survival of patients with non-small cell lung cancer, but is also closely related to the success of other immunotherapies. IL-21 can promote the proliferation and function of T cells, B cells, and natural killer (NK) cells, thereby enhancing the anti-tumor activity of the tumor immune microenvironment. In this study, the increase in circulating IL-21 levels was significantly correlated with longer progression-free survival and overall survival, suggesting that IL-21 may be a key effector factor in radio-immunotherapy.
In addition, the study also revealed the association between changes in IL-8 and exosomal PD-L1 levels and treatment prognosis. The decrease in IL-8 is related to better efficacy of immunotherapy, while the reduction in exosomal PD-L1 means the weakening of tumor immunosuppressive signals. These data further illustrate that in addition to IL-21, other cytokines and immunomodulatory factors may jointly affect the efficacy of radio-immunotherapy.
Outlook and Summary
The SWORD study provides valuable clinical data for the field of radio-immunotherapy, further confirming the efficacy of the triplet combination of SBRT, PD-1 inhibitors, and GM-CSF. However, how to fully utilize Tfh cells and their related immune signaling pathways, and optimize treatment doses and regimens, remains the focus of future research. With the development of precision medicine and immunology, radio-immunotherapy is expected to become an important treatment modality for patients with metastatic NSCLC and other advanced solid tumors.
This study opens the door to a new era of radio-immunotherapy. Future research will be dedicated to better understanding and utilizing the potential of this treatment strategy, promoting the development of personalized and precise treatment, and benefiting more patients.
Literature Learning Insights from the PRaG Team
As two clinical trials conducted concurrently, the SWORD study and the PRaG study (PD-1 inhibitor, Radiotherapy, and GM-CSF, PRaG) both independently chose the triplet therapy of hypofractionated radiotherapy, GM-CSF, and PD-1 inhibitors for the treatment of refractory tumors, and both obtained encouraging data [2]. Compared with historical controls of single-agent immunotherapy, the ORR significantly improved, while the toxic side effects remained within a controllable range, indicating the good tolerability and effectiveness of this treatment strategy. In addition, the SWORD study also found that stereotactic body radiotherapy significantly increased follicular helper T cells (Tfh) in distant lesions and IL-21 in the peripheral blood of patients, indicating a stronger anti-cancer immune response.
Hypofractionated radiotherapy can promote antigen exposure and produce an in situ vaccine effect. The radiotherapy lesion in this study adopted an irradiation of 8Gy*3f, which has been proven to activate the cGAS-STING signaling pathway and activate anti-tumor immune responses [3], which is also consistent with the dose in the PEMBRO-RT study [4]. GM-CSF can promote the functional activation of antigen-presenting cells, especially dendritic cells, and enhance antigen presentation [5]. In previous studies, GM-CSF combined with radiochemotherapy produced a distant effect of 26.8% [6]. Although this study did not significantly improve ORR and OS compared with dual therapy (PD-1 antibody combined with hypofractionated radiotherapy), the patients in this study group had a higher tumor burden, suggesting that GM-CSF may be playing a potential role.
Compared with the PRaG 1.0 study, although both studies adopted a triplet therapy model, there are still some differences.
Firstly, in terms of the enrolled population, the SWORD study enrolled driver gene-negative NSCLC patients who failed first-line chemotherapy, making the enrolled population lung cancer patients, which is convenient for efficacy comparison with other studies. In contrast, the PRaG 1.0 study enrolled pan-tumor patients, although it has broader applicability, it is difficult to draw clear conclusions. Both studies enrolled patients with advanced tumors with a high tumor burden, but the tumor burden in the SWORD study was higher than that in the PRaG study. However, the ECOG score in the SWORD study was 0-1, while the PRaG study enrolled patients with 0-3, of which 70% or more were 2-3, and more than 65% were 4th line and above treatment lines. The general condition of patients enrolled in the PRaG study was worse.
Secondly, in terms of treatment regimen, the SWORD triplet therapy was performed for the first cycle, and subsequent PD-1 inhibitor maintenance therapy was given. During the triplet therapy cycle, SBRT treatment was performed first, followed by PD-1 inhibitor and GM-CSF treatment within two weeks. This may be because the researchers considered that most of the enrolled patients had chest radiotherapy, and simultaneous radio-immunotherapy may increase the incidence of immune-mediated pneumonitis. Therefore, a sequential treatment model was adopted, but antigen exposure has a certain timeliness. As shown in the subgroup analysis of the PACIFIC study, patients with an interval of more than two weeks between concurrent chemoradiotherapy and immunotherapy had relatively poor prognosis [7]. SWORD stipulated that PD-1 inhibitors and GM-CSF treatment should be performed within two weeks, which shows the rigor of the researchers’ design. In the PRaG study, a triplet therapy of at least two cycles, with irradiation of at least two lesions, was adopted, mainly considering the heterogeneity between different metastatic lesions and increasing tumor antigen exposure. By performing radiotherapy on different sites in multiple cycles, compared with irradiating multiple lesions simultaneously, it can further increase the treatment tolerance of patients with poor general condition in the advanced stage, and reduce the irradiation range of low-dose areas, which may also minimize the lymphocyte reduction caused by radiotherapy.
Thirdly, in terms of efficacy, in the SWORD study, among 49 evaluable patients, the ORR was 36.7%, with no CR patients. In the PRaG study, among 48 evaluable patients, the ORR was 18.8%, with three CR patients. In the PRaG study, the irradiated lesions were excluded from the target lesions for efficacy evaluation. The observation of abscopal effects found that the ASR (abscopal tumor regression) in the SWORD study was 30.6%, and the ASR in the PRaG study was 20.8% (10/48). Both studies observed a higher incidence of abscopal effects, which is similar to the reported abscopal effects of PD-1 inhibitors combined with radiotherapy. It may also be the potential role of GM-CSF (ASR comparison: Jianjao Ni, 30.6%, NSCLC; vs. Jason J. Luke, 27%, Advanced Solid Tumors; vs. Yuehong kong, 20.8%, Advanced Solid Tumors; vs. Encouse B Golden, 26.8%, Advanced Solid Tumors) [1,2,8,6].
Fourthly, in terms of safety, the triplet therapy model is generally safe and controllable. Adverse reactions are mainly grade 1-2. In addition to common fatigue, fever, and bone pain, the SWORD study reminded to pay attention to heart failure, and the PRaG study reminded to pay attention to transient pulse oxygen desaturation.
Finally, another highlight of the SWORD study is that it conducted many biomarker analyses, while the PRaG study only conducted simple hematological biomarker analyses. The Tfh/IL-21 pathway discovered in the SWORD study may be related to the immune activation response triggered by SBRT. Previous studies have reported that the number of tumor-infiltrating CXCR5+CD8+T cells is associated with better prognosis [9]. In patients with hematological malignancies, CXCR5+PD-1+CD8+T cells were found to be related to the efficacy of PD-1 inhibitors [10]. Tfh (CXCR5+CD4+T) cells can aggregate in the tumor bed of tumor-draining lymph nodes and produce interleukin-21 (IL-21). IL-21 can maintain T cell stemness and inhibit T cell exhaustion, which is of important significance [11]. Its mechanism is worth further exploration.
The SWORD study provides valuable clinical data for the triplet therapy model of radio-immunotherapy combined with cytokines. How to optimize the combination model in the future, including different radiotherapy fractionation doses, comparison of high and low doses, partial irradiation, etc., and the timing of GM-CSF use, whether using it prior to radiotherapy or concurrently with radiotherapy can play a greater role is still unclear. In addition, whether the application of other cytokines will enhance efficacy is worth further exploration. Research on new biomarkers and mechanisms of radio-immunotherapy has always been a research hotspot, and it will also help guide clinical treatment strategies.
PRaG Treatment Center, The Second Affiliated Hospital of Soochow University Kong Yuehong, Zhang Liyuan
