Preclinical and clinical evidence suggests that intestinal low-dose radiotherapy (ILDR) may enhance antitumor immune responses by modulating the gut microenvironment, thereby improving the efficacy of immune checkpoint inhibitors (ICBs) in refractory solid tumors. Based on these findings, the investigators initiate a multicohort phase II clinical trial to evaluate the clinical benefit and safety of ILDR combined with PD-1/PD-L1 monoclonal antibody therapy in patients with metastatic solid tumors resistant to prior ICB treatment.
In this study, patients are stratified into three parallel cohorts by tumor type (lung cancer, esophageal cancer, and other solid tumors), with 16 patients per cohort (48 in total, including subjects enrolled from the ILDR-01 study). Eligible participants includes patients with advanced metastatic solid tumors progressing after monotherapy or combination ICB treatment, meeting criteria of ECOG performance status 0-2, life expectancy ≥3 months, and have at least one measurable lesion. Exclusion criteria encompasses prior pelvic radiotherapy, ongoing infections, major organ dysfunction, or concurrent antitumor therapies.
The primary endpoints includes objective response rate (ORR), disease control rate (DCR), progression-free survival after ILDR (PFS2), and the incidence of abscopal effects. Secondary endpoints includes overall survival (OS), treatment safety, α/β diversity changes in gut microbiota, peripheral blood immune cell subset dynamics, and tumor immune microenvironment remodeling characteristics. All patients receives a 1 Gy jejunoileal radiotherapy followed by PD-1/PD-L1 monoclonal antibody administration (in accordance to prior protocols or guidelines) within 24 hours, with maintenance therapy up to 2 years. Therapeutic efficacy is assessed via RECIST v1.1, while therapeutic toxicity is assessed according to CTCAE v5.0.
Paired pre- and post-treatment samples (including wumor tissue, stool, peripheral blood etc.) are collected for metagenomic sequencing, metabolomic analysis, and multi-omics integrative modeling to systematically elucidate the regulation mechanism of gut microbiota-metabolite-immune axis mediated by ILDR. This approach aims to provide theoretical foundations for optimizing treatment strategies in immunotherapy-resistant tumors and identify biomarkers that potentially associated with therapeutic efficacy.
Age ≥18 years, ≤80 years, regardless of gender.
ECOG level 0-2.
Expected life span>3 months.
At least one accessible and measurable lesion should be selected as the target lesion for observation according to RECIST criteria.
Patients with contraindications to radiation therapy and immunotherapy.
Previous occurrence of unacceptable immune related toxic side effects (immune myocarditis, pneumonia, etc.).
Patients who were assessed as hyperprogressive disease (HPD).
Patients who have received pelvic and abdominal radiation therapy within 6 months prior to enrollment.
Parallel
Low-dose radiotherapy to the intestine (ILDR)
RadiationA single total dose of 1 Gy irradiation targeting the jejunum and ileum. Primary tumor or metastatic lesions that are within the irradiation field are irradiated concurrently.
PD-1/PD-L1 monoclonal antibodies
DrugPre-progression immunotherapy regimen continues or switches to an alternative PD-1/PD-L1 monoclonal antibody according to clinical guidelines.PD-1/PD-L1 monoclonal antibody will be given 1 day after ILDR at a 3-week interval.
Objective Response Rate (ORR)
Proportion of patients achieving complete response (CR) or partial response (PR) (sustained ≥4 weeks) per RECIST v1.1.
Disease Control Rate（DCR）
Proportion of patients with CR, PR, or stable disease (SD) per RECIST v1.1.
Progression Free Survival while Receiving ILDR combined Therapy (PFS2)
Time from ILDR treatment to second documented disease progression (assessed by investigator via PSA, imaging, symptom, or the combinations) or death from any cause.
Incidence of Abscopal Effect
Proportion of patients demonstrating tumor response in one or more non-irradiated lesions.
Overall Survival (OS)
Time from ILDR treatment initiation to death from any cause.
Cancer-Specific Survival (CSS)
Time from ILDR treatment initiation to death due to cancer.
Adverse Events
Proportion of patients with treatment-related adverse events as assessed by CTCAE v5.0.
Peripheral Blood Analyses
Peripheral blood analysis includes immune profiling, transcriptomics, immune receptor repertoire, metabolomics, and cytokine analysis
Tissue Analyses
Tissue analyses includes transcriptomics, immune receptor repertoire, and immunohistochemistry.
Fecal Analyses
Fecal analyses include fecal metagenomics and fecal metabolomics.
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Chuangzhen Chen
Lead sponsor
Shantou University Medical College
Sponsor institution
