Endostar combined with PD-1 blockade, radiotherapy, GM-CSF, and IL-2 (PRaG 2.0E) for refractory non-small cell lung cancer: a single-arm, phase II clinical trial (PRaG2.0E Study Protocol)

Introduction

Background

In the evolving landscape of thoracic oncology, immune checkpoint inhibitors (ICIs) have revolutionized the therapeutic paradigm for advanced non-small cell lung cancer (NSCLC) (1), offering significant survival benefits to a subset of patients. However, a substantial proportion of patients exhibits primary resistance to ICI monotherapy or develop acquired resistance, eventually leading to disease progression (2). Mechanistic investigations have identified the heterogeneity and immunosuppressive nature of the tumor immune microenvironment (TIME) as critical bottlenecks limiting immunotherapy efficacy (3). Advanced refractory NSCLC typically manifests with “immune-desert” or “immune-excluded” phenotypes, characterized by an enrichment of immunosuppressive cells—such as regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs)—and a paucity or exhaustion of effector T cells (Teffs) (4-7). Consequently, isolated blockade of the programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) pathway is often insufficient to reverse this profound immunosuppression.

Rationale and knowledge gap

In the post-immunotherapy era, salvage strategies that breach immune tolerance and convert “cold” tumors into “hot” ones via combinatorial approaches have become an urgent clinical necessity (8). The “PRaG” regimen—a multimodal strategy comprising PD-1 inhibitors, radiotherapy (RT), and granulocyte-macrophage colony-stimulating factor (GM-CSF)—was developed to address this need. In this synergistic “cocktail”, RT acts as an in situ vaccine to induce immunogenic cell death (ICD) and release tumor-associated antigens (TAAs) (9); GM-CSF functions as an immune adjuvant to promote dendritic cell (DC) maturation and antigen presentation; and PD-1 inhibitors reverse T-cell exhaustion. To further augment this effect, the updated “PRaG 2.0” regimen incorporates interleukin-2 (IL-2). As a critical T-cell growth factor, IL-2 is essential for the proliferation and activation of CD8⁺ cytotoxic T cells and CD4⁺ Th1 cells (10,11), thereby providing the metabolic support necessary for a sustained antitumor immune response.

Despite these advances, the abnormal tumor vasculature remains a formidable physical barrier. Advanced tumors are characterized by chaotic, leaky vessels that create high interstitial fluid pressure and severe hypoxia (12). This hypoxic microenvironment not only upregulates immunosuppressive factors (e.g., VEGF, TGF-β) via the HIF-1α pathway but also mechanically impedes the infiltration of effector immune cells (13,14). Recombinant human endostatin (Endostar), a multi-target endogenous anti-angiogenic agent, addresses this challenge through “vascular normalization” rather than simple vessel ablation. By pruning immature vessels and restoring vascular structure, Endostar improves oxygenation and drug delivery while facilitating the transendothelial migration of CD8⁺ T cells (15,16). Research indicates that the “vascular normalization window” induced by Endostar typically opens in the early phase following administration. The 72-hour continuous infusion method ensures that the plasma drug concentration remains consistently above the effective threshold for inducing normalization throughout the entire course of RT. This high degree of temporal synchronization ensures that when subjected to high-dose irradiation, the tumor tissue is continuously maintained in an optimal state of improved blood perfusion and enhanced oxygenation, thereby overcoming hypoxia-induced radioresistance to a certain extent (17).

Objective

Building on these rationales, this study proposes the PRaG 2.0E regimen, which integrates Endostar with the PRaG 2.0 therapy. This innovative strategy aims to systematically repair critical breakpoints in the ‘Cancer-Immunity Cycle’ (18)—from antigen release and presentation to T-cell trafficking and cytotoxicity. By leveraging the multidimensional synergy of “radiotherapy-antiangiogenesis-immunotherapy”, PRaG 2.0E seeks to overcome both immune tolerance and physical barriers, offering a potent, systemic salvage therapy for patients with advanced refractory NSCLC.

The objective of this study is to investigate the efficacy of recombinant human endostatin (Endostar) combined with hypofractionated radiotherapy (HFRT) and sequential PD-1/PD-L1 inhibitor and GM-CSF therapy for the treatment of advanced refractory NSCLC, while simultaneously evaluating the safety profile and associated adverse events (AEs) of this regimen. We present this article in accordance with the SPIRIT reporting checklist (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0203/rc).

Methods

Study design

This is a single-center, prospective, single-arm, phase II clinical trial. Eligible patients with advanced refractory NSCLC will be screened and enrolled after providing written informed consent. Participants will receive treatment comprising recombinant human endostatin (Endostar) in combination with the “PRaG2.0” regimen. Radiological tumor assessments will be performed every 6 weeks according to RECIST 1.1, irRECIST, and iRECIST criteria. Safety will be evaluated using the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) version 5.0, with AEs recorded throughout the study period and up to 90 days post-treatment. Following the completion of treatment, all subjects will undergo survival follow-up every 6 weeks until death, loss to follow-up, withdrawal of consent, or study termination by the sponsor.

RECIST 1.1 is the gold standard for evaluating the response of solid tumors to conventional cytotoxic chemotherapy. It is based solely on the change in tumor burden as measured by anatomic imaging (CT/MRI). It defines response based on the change in the sum of diameters of target lesions.

• Complete response (CR): disappearance of all target lesions.
• Partial response (PR): ≥30% decrease in the sum of diameters.
• Progressive disease (PD): ≥20% increase in the sum of diameters (and at least 5 mm absolute increase) or the appearance of new lesions.
• Stable disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD.

The NCI-CTCAE is the standardized clinical nomenclature and grading system for reporting AEs in cancer clinical trials and research. The system utilizes a 5-point severity scale.

• Grade 1 (mild): asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention not indicated.
• Grade 2 (moderate): minimal, local, or noninvasive intervention indicated; limiting age-appropriate instrumental activities of daily living (ADL).
• Grade 3 (severe): severe or medically significant but not immediately life-threatening; hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care ADL.
• Grade 4 (life-threatening): life-threatening consequences; urgent intervention indicated.
• Grade 5 (death): death related to the AE.

Study endpoints

The primary endpoint of this study will be the overall response rate (ORR), defined as the proportion of evaluable patients achieving a best overall response of CR or PR, assessed according to RECIST version 1.1. Secondary endpoints will include progression-free survival (PFS), disease control rate (DCR), overall survival (OS), and the incidence of treatment-related toxicities. The incidence of treatment-related toxicities will be calculated as the proportion of evaluable patients experiencing treatment-related AEs, assessed according to the CTCAE version 5.0.

The exploratory translational research indicators of this study primarily encompass T lymphocyte subsets, tumor-specific cytotoxic T cells, activated cytotoxic T lymphocytes, activated memory T cells, monocytes, and DCs. Furthermore, a comprehensive cytokine profile will be assessed, including IL-2, IL-4, IL-6, IL-10, IL-17A, TNF-α, and IFN-γ. Peripheral blood and/or tissue specimens are required to be collected at the protocol-specified time points and processed in strict accordance with the defined procedures to facilitate subsequent translational analyses.

Inclusion criteria

The inclusion criteria for this study will be as follows: (I) Patients aged 18 to 75 years. (II) Patients were histologically or cytologically confirmed recurrent or metastatic advanced NSCLC, and had been previously treated with platinum-based doublet chemotherapy and ICIs. Eligible patients must have no standard treatment options recommended by guidelines or be intolerant to standard therapies. Additionally, patients must have at least one measurable metastatic lesion (>1 cm). (III) No history of congestive heart failure, unstable angina, or unstable arrhythmia within the 6 months prior to enrollment. The baseline troponin level of the patient needs to be lower than the upper limit of the normal reference range (>99th percentile), and the left ventricular ejection fraction (LVEF) on echocardiography needs to be greater than 55%, without new wall motion abnormalities (myocardial ischemia), moderate to severe pericardial effusion, or severe structural heart disease. (IV) An Eastern Cooperative Oncology Group (ECOG) performance status of 0–3 and a life expectancy of ≥3 months. (V) No history of severe hematopoietic, cardiac, pulmonary, hepatic, or renal dysfunction, or immunodeficiency. (VI) Within one week prior to enrollment, patients must meet the following laboratory criteria: absolute T-lymphocyte count ≥0.5 times lower limit of normal (LLN); neutrophil count ≥1.0×10⁹/L; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 × upper limit of normal (ULN) (or ≤ 5.0 × ULN for patients with liver cancer or liver metastases); serum creatinine ≤3.0 times ULN. (VII) Patients must have the ability to understand and voluntarily sign the informed consent form.

Exclusion criteria

The exclusion criteria for this study will be as follows: (I) Female patients who were pregnant or breastfeeding. (II) History of other malignancies within the past 5 years, with the exception of adequately treated cutaneous carcinoma or carcinoma in situ of the cervix. (III) History of uncontrolled epilepsy, central nervous system (CNS) diseases, or psychiatric disorders that, in the judgment of the investigator, are clinically severe enough to prevent the signing of informed consent or compromise compliance with the study treatment. (IV) Clinically significant (active) cardiac disease, including symptomatic coronary artery disease, congestive heart failure classified as New York Heart Association (NYHA) class II, severe arrhythmia requiring pharmacological intervention, or a history of myocardial infarction within the past 12 months. The baseline troponin level of the patient is higher than the upper limit of the normal reference range (> 99th percentile), or the echocardiogram indicated that the LVEF was <50%, there was new wall motion abnormality (myocardial ischemia), moderate to severe pericardial effusion, or severe structural heart disease. (V) History of organ transplantation requiring immunosuppressive therapy. (VI) Known significant active infection, or major hematological, renal, metabolic, gastrointestinal, or endocrine dysfunction/disorders, or other severe uncontrolled concomitant diseases as assessed by the investigator. (VII) Known allergy or hypersensitivity to any components of the study drug. (VIII) History of immunodeficiency, including a positive test for human immunodeficiency virus (HIV), other acquired or congenital immunodeficiency diseases, history of organ transplantation, or other immune-related diseases requiring long-term oral hormone therapy. (IX) Active acute or chronic tuberculosis (TB) infection (defined as a positive T-SPOT test or suspicious tuberculous lesions on chest radiography). (X) Any other condition that, in the opinion of the investigator, rendered the patient unsuitable for enrollment.

Treatment scheme

Enrolled patients will receive treatment according to the PRaG 2.0E regimen, as described below:

• RT will be initiated on Day 1 of treatment. A primary or metastatic lesion that has not been previously irradiated and poses minimal risk to surrounding normal tissues will be selected for treatment. The total radiation dose will range from 10 to 24 Gy, administered in 2 to 3 fractions (10–24 Gy/2–3 f) with a fractional dose of 5–8 Gy, and will be delivered once daily (target selection principles: priority will be given to lesions where damage to surrounding normal tissues can be minimized. Among eligible lesions, larger ones will be preferred, with a recommended maximum diameter of 4 cm).
• Recombinant Human Endostatin (Endostar) will be initiated on Day 1, administered as a continuous intravenous infusion (CIV) of 210 mg over 72 hours.
• GM-CSF will be administered subcutaneously (200 µg daily) for 7 consecutive days, starting on the first day following the completion of RT.
• IL-2 will be administered subcutaneously (2 million IU daily) for 7 consecutive days, starting on the day immediately following the completion of GM-CSF treatment.
• PD-1 inhibitor will be administered within one week after the completion of RT.

Each treatment cycle will be 21 days. Patients will receive the combination therapy for a minimum of 2 cycles. Subsequently, maintenance therapy consisting of the PD-1 inhibitor combined with Endostar will be continued until disease progression or the occurrence of intolerable toxicity. The specific treatment protocol is shown in Figure 1.

Figure 1 Planned study protocol. CIV, continuous intravenous infusion; d, day; GM-CSF, granulocyte-macrophage colony-stimulating factor; IL-2, interleukin-2; PD-1, programmed cell death protein 1; PD-L1, programmed death-ligand 1; PRaG, PD-1 inhibitor, radiotherapy, and GM-CSF; q3w, once every 3 weeks.

Adjustment of drug dosage

For toxicities that the investigator deems unlikely to result in serious or life-threatening events and that will not delay or interrupt treatment (e.g., fatigue, alopecia, dysgeusia), the study drug should not be dose-reduced or withheld; treatment should continue at the original dose.

If the investigator assesses that an adverse event (AE) is concurrently related to recombinant human endostatin, RT, and the anti-PD-1/PD-L1 inhibitor, a comprehensive evaluation must be performed to determine which treatment has a stronger causal relationship with the AE and leads to more severe consequences, and dose modification should be prioritized for that specific treatment.

Sample size calculation

The sample size for this study is determined using Simon’s two-stage optimal design to test the null hypothesis that the objective response rate (ORR) is historically uninteresting (≤10%; P₀=0.10) against the alternative hypothesis that the regimen warrants further investigation (≥30%; P₁=0.30). The statistical parameters will be established with a one-sided type I error rate (α) of 0.05 and a statistical power (1-β) of 80%. In the first stage, 10 evaluable patients will be enrolled; if no objective responses are observed (0 responses), the study will be terminated early for futility. Under this design, the probability of early termination under the null hypothesis is 34.9%, yielding an expected sample size (EN0) of 23.03 evaluable patients. If at least one response (≥1) is documented, the study will proceed to the second stage, enrolling an additional 20 patients for a total sample size of 30 evaluable patients. At the final analysis, if 6 or more patients out of 30 achieve a confirmed objective response (CR or PR), the null hypothesis will be rejected, and the PRaG 2.0E regimen will be considered to possess sufficient clinical activity. To account for a potential dropout or non-evaluable rate of approximately 10%, we anticipate screening and enrolling a total of 33 patients to ensure 30 evaluable subjects are included in the final efficacy analysis.

Statistical analysis

Data analysis will be performed using SPSS software, version 18.0. The normality of residuals will be assessed using the Shapiro-Wilk test (significance level α>0.05). Variables conforming to a normal distribution will be analyzed using randomized block analysis of variance (ANOVA), while non-normally distributed variables will be analyzed using rank-sum tests for randomized block design (significance level α<0.05). These methods will be used to compare changes in white blood cell (WBC) counts, granulocyte counts, lymphocyte and lymphocyte subset counts, and cytokine levels before and after RT. Cox proportional hazards regression analysis will be conducted to evaluate the impact of changes in the aforementioned cell counts and cytokine levels (pre- and post-RT) on patient survival. The Kaplan-Meier method will be used to compare survival rates between patients who experience the abscopal effect and those who do not, as well as to analyze the relationship between patient survival and relevant cytokines. Efficacy analysis will be primarily based on the Full Analysis Set (FAS). Patients who receive at least one dose of study treatment but fail to undergo any post-baseline radiological assessment due to loss to follow-up, withdrawal of consent, or death will be conservatively classified as non-responders for the primary endpoint of ORR. All dropouts will be documented by the study coordinators with specific reasons (e.g., AEs, protocol deviation) and included in the safety analysis. For exploratory biomarkers, minor missing data will be addressed using the Last Observation Carried Forward (LOCF) method, and sensitivity analyses will be performed to ensure the robustness of the clinical conclusions.

Monitoring of the research

Subject to compliance with local patient confidentiality regulations, the responsible monitor will regularly contact and visit the investigator, and shall be permitted to inspect various trial records [Case Report Forms (CRFs) and other relevant data] upon request.

This study builds upon the accumulated experience from PRaG 2.0; our center has recruited two research assistants exclusively dedicated to clinical trial quality control and coordination. Throughout the duration of the study, the monitor is responsible for routinely reviewing the CRFs, verifying patient compliance with the study protocol, and checking the completeness, consistency, and accuracy of the entered data. The monitor shall be granted access to laboratory test reports and other patient records (source documents) to verify the data entries on the CRFs. The investigator (or their designee) agrees to cooperate with the monitor to ensure that any issues identified during these monitoring visits are resolved.

Patient and public involvement

We will implement a structured patient experience survey to be administered after the second cycle of treatment to capture real-time feedback on the burden of the “PRaG 2.0E” regimen, which will be used to inform future protocol amendments.

Ethics and dissemination

The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by The Ethics Committee of the Second Affiliated Hospital of Soochow University (No. JD-LK2022173-IR01) and informed consent will be obtained from all individual participants before the trial. The results of the PRaG2.0E study, regardless of the outcome, are intended to be published in a peer-reviewed international medical journal. Upon publication of the primary trial results, de-identified individual participant data (IPD) that underlie the results reported in this article will be made available to researchers who provide a methodologically sound proposal. Data will be made available beginning 6 months and ending 3 years following the article’s publication. The data access link will be announced in the research results publication article. The reporting of the trial’s findings will adhere strictly to the guidelines set forth in the Consolidated Standards of Reporting Trials (CONSORT) statement. The study is registered in ClinicalTrials. gov (NCT06047860).

Discussion

This study evaluates the PRaG 2.0E regimen, a novel combinatorial strategy designed to overcome the multidimensional resistance mechanisms in refractory NSCLC. The rationale relies on a closed-loop synergy: RT serves not only for local cytoreduction but also as an immune primer triggering ICD and releasing TAAs and damage-associated molecular patterns (DAMPs). Within this framework, GM-CSF recruits and matures DCs to enhance antigen presentation, while IL-2 provides the necessary signals for the expansion of Teffs and natural killer (NK) cells. Concurrently, ICIs relieve the “brakes” imposed by the PD-1/PD-L1 axis.

Previous clinical data on the original PRaG regimen in patients with advanced refractory solid tumors demonstrated promising efficacy, yielding an ORR of 16.7%, a DCR of 46.3%, a median progression-free survival (mPFS) of 4.0 months, and a median overall survival (mOS) of 10.5 months. The safety profile was manageable, with the incidence of grade ≥3 adverse events limited to 8.0% (19). Specifically, in the NSCLC subgroup, the DCR reached 50.0%. Building on these findings, the PRaG 2.0 regimen incorporates IL-2 to further potentiate immune effector function, a strategy supported by evidence of its synergy with hypofractionated RT (20) and GM-CSF (21). Notably, this optimized PRaG 2.0 regimen has demonstrated improved clinical outcomes, achieving an ORR of 22.7% and a DCR of 56.1%.

A critical innovation of the PRaG 2.0E regimen is the incorporation of Endostar to target the tumor vasculature. Beyond its anti-angiogenic properties, Endostar promotes vascular normalization, thereby alleviating hypoxia—a known driver of radioresistance and immune suppression. Clinical evidence indicates that Endostar combined with RT significantly improves outcomes in NSCLC patients with brain metastases (22), and recent data from the 2022 European Society for Medical Oncology(ESMO) Congress highlight its synergy with PD-1 inhibitors in the first-line setting. By integrating Endostar, PRaG 2.0E aims to dismantle the physical vascular barrier, facilitating the infiltration of the expanded T-cell population into the tumor core.

Safety is a paramount consideration in this multi-agent protocol. Drawing upon lessons from trials of stereotactic body radiation therapy (SBRT) combined with immunotherapy (23,24), we employ a sequential administration strategy. By optimizing the timing of RT and the cycling of cytokines, we aim to minimize the risk of overlapping toxicities, such as cytokine release syndrome. Given that Endostar, GM-CSF, and IL-2 have well-characterized safety profiles, we anticipate that rigorous clinical monitoring will maintain risks within tolerable limits.

Furthermore, this study emphasizes translational research. We will conduct longitudinal monitoring of peripheral blood biomarkers, including T-lymphocyte subsets, MDSCs, and cytokine profiles. These analyses are crucial for elucidating the biological mechanisms driving response and resistance, and for identifying predictive biomarkers to guide patient selection.

In conclusion, the PRaG 2.0E regimen represents a paradigm shift from monotherapy to a comprehensive, mechanistically grounded combination strategy. If this study demonstrates improved ORRs and survival with acceptable toxicity, it will provide high-level evidence to support this “vascular-immune-radiotherapy” model as a viable salvage option for patients with advanced refractory NSCLC.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the SPIRIT reporting checklist. Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0203/rc

Peer Review File: Available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0203/prf

Funding: This work was supported by Clinical Research Fund of the China International Medical Exchange Foundation (No. Z-2014-06-2202); Open Project of the State Key Laboratory of Radiology and Radiation Protection of Soochow University (Nos. GZK12025064, GZK1202238); Suzhou Science and Technology Development Plan (No. SKY2022163).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-2026-1-0203/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study will be conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of The Second Affiliated Hospital of Soochow University (No. JD-LK2022173-IR01) and informed consent will be obtained from all individual participants.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Reck M, Rodríguez-Abreu D, Robinson AG, et al. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med 2016;375:1823-33. [Crossref] [PubMed]
2. Sharma P, Hu-Lieskovan S, Wargo JA, et al. Primary, Adaptive, and Acquired Resistance to Cancer Immunotherapy. Cell 2017;168:707-23. [Crossref] [PubMed]
3. Chen DS, Mellman I. Elements of cancer immunity and the cancer-immune set point. Nature 2017;541:321-30. [Crossref] [PubMed]
4. Chen K, Luo L, Li Y, et al. Reprogramming the immune microenvironment in lung cancer. Front Immunol 2025;16:1684889. [Crossref] [PubMed]
5. Wang Z, Du X, Xing X, et al. Myeloid-Derived Suppressor Cells: Orchestrators of Tumor Immune Evasion and Therapeutic Vulnerabilities. Mol Cancer Res 2025;23:829-38. [Crossref] [PubMed]
6. Chow A, Perica K, Klebanoff CA, et al. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat Rev Clin Oncol 2022;19:775-90. [Crossref] [PubMed]
7. Nishikawa H, Koyama S. Mechanisms of regulatory T cell infiltration in tumors: implications for innovative immune precision therapies. J Immunother Cancer 2021;9:e002591. [Crossref] [PubMed]
8. Wu B, Zhang B, Li B, et al. Cold and hot tumors: from molecular mechanisms to targeted therapy. Signal Transduct Target Ther 2024;9:274. [Crossref] [PubMed]
9. Kong YH, Ma YF, Zhao XR, et al. Research progress on application of radiotherapy to sensitize PD-1/PD-L1 inhibitors. Chinese Journal of Radiation Oncology 2021;30:984-8.
10. Boyman O, Kolios AG, Raeber ME. Modulation of T cell responses by IL-2 and IL-2 complexes. Clin Exp Rheumatol 2015;33:S54-7.
11. Tanigawa K, Redmond WL. Current landscape and future prospects of interleukin-2 receptor (IL-2R) agonists in cancer immunotherapy. Oncoimmunology 2025;14:2452654. [Crossref] [PubMed]
12. Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 2014;26:605-22. [Crossref] [PubMed]
13. Fukumura D, Kloepper J, Amoozgar Z, et al. Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges. Nat Rev Clin Oncol 2018;15:325-40. [Crossref] [PubMed]
14. Qian C, Liu C, Liu W, et al. Targeting vascular normalization: a promising strategy to improve immune-vascular crosstalk in cancer immunotherapy. Front Immunol 2023;14:1291530. [Crossref] [PubMed]
15. Chu XD, Bao H, Lin YJ, et al. Endostatin induces normalization of blood vessels in colorectal cancer and promotes infiltration of CD8+ T cells to improve anti-PD-L1 immunotherapy. Front Immunol 2022;13:965492. [Crossref] [PubMed]
16. Tartour E, Pere H, Maillere B, et al. Angiogenesis and immunity: a bidirectional link potentially relevant for the monitoring of antiangiogenic therapy and the development of novel therapeutic combination with immunotherapy. Cancer Metastasis Rev 2011;30:83-95. [Crossref] [PubMed]
17. Zhai Y, Ma H, Hui Z, et al. HELPER study: A phase II trial of continuous infusion of endostar combined with concurrent etoposide plus cisplatin and radiotherapy for treatment of unresectable stage III non-small-cell lung cancer. Radiother Oncol 2019;131:27-34. [Crossref] [PubMed]
18. Chen DS, Mellman I. Oncology meets immunology: the cancer-immunity cycle. Immunity 2013;39:1-10. [Crossref] [PubMed]
19. Kong Y, Zhao X, Xu M, et al. PD-1 Inhibitor Combined With Radiotherapy and GM-CSF (PRaG) in Patients With Metastatic Solid Tumors: An Open-Label Phase II Study. Front Immunol 2022;13:952066. [Crossref] [PubMed]
20. Jing H, Hettich M, Gaedicke S, et al. Combination treatment with hypofractionated radiotherapy plus IL-2/anti-IL-2 complexes and its theranostic evaluation. J Immunother Cancer 2019;7:55. [Crossref] [PubMed]
21. Yu AL, Gilman AL, Ozkaynak MF, et al. Anti-GD2 antibody with GM-CSF, interleukin-2, and isotretinoin for neuroblastoma. N Engl J Med 2010;363:1324-34. [Crossref] [PubMed]
22. Chen L, Tong F, Peng L, et al. Efficacy and safety of recombinant human endostatin combined with whole-brain radiation therapy in patients with brain metastases from non-small cell lung cancer. Radiother Oncol 2022;174:44-51. [Crossref] [PubMed]
23. Schild SE, Wang X, Bestvina CM, et al. Alliance A082002 -a randomized phase II/III trial of modern immunotherapy-based systemic therapy with or without SBRT for PD-L1-negative, advanced non-small cell lung cancer. Clin Lung Cancer 2022;23:e317-20. [Crossref] [PubMed]
24. Luke JJ, Lemons JM, Karrison TG, et al. Safety and Clinical Activity of Pembrolizumab and Multisite Stereotactic Body Radiotherapy in Patients With Advanced Solid Tumors. J Clin Oncol 2018;36:1611-8. [Crossref] [PubMed]