Intestinal Low Dose Radiotherapy Combined With Immunotherapy in Immune-resistant Metastatic Malignant Solid Tumors

Efficacy and Safety of Combining Intestinal Low Dose Radiotherapy and PD-1/PD-L1 Inhibitors for Metastatic Malignant Solid Tumors After Acquired Resistance to Anti-PD1/PD-L1 Treatment

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.

Inclusion Criteria:

• 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 metastatic solid tumors (of any histology) without standard therapy options, who have previously received immunotherapy, immunotherapy combined with chemotherapy, or immunotherapy combined with anti-angiogenesis treatment and have shown disease progression.
• Patients should not be considered eligible for surgical treatment.
• Patients with brain metastases that are assessed as clinically stable after treatment through repeated CT and/or MRI scans are eligible.
• Patients have complete clinical and pathological information.
• Patients should not be borthered by any psychological, family, social or geographical conditions that may hinder compliance with the research protocol.
• Patients should be able to understand the informed consent form, voluntarily participate, and sign the informed consent form.
• Other indicators accord with the general inclusion criteria for clinical trials.

Exclusion 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.
• The adverse reactions from prior treatment have not yet recovered to a CTCAE5.0 rating of ≤ 1 (excluding toxicity that has been determined to be risk-free, such as fatigue or hair loss).
• Patients with active uncontrolled systemic bacterial, viral, or fungal infections despite optimal treatment.
• Significant liver or kidney dysfunction (i.e., laboratory values >3 times the upper limit of normal).
• Active hepatitis B, hepatitis C, HIV, or syphilis.
• Brain disorders, symptomatic central nervous system (CNS) or meningeal metastases, or impaired cognitive function.
• Hypersensitivity to any drug included in the trial.
• Drug and/or alcohol abuse.
• Pregnant or breastfeeding women.
• Concurrent participation in another therapeutic clinical trial.
• Poorly controlled pleural effusion, pericardial effusion, or ascites requiring frequent drainage (recurrence within ≤14 days after intervention).
• Major surgery within 30 days.
• Use of antibiotics, antifungals, antivirals, antiparasitics, or probiotics within 4 weeks before enrollment.