Oncolytic Virus (H101) + SBRT + Chemotherapy + Targeted Therapy + Immunotherapy for Unresectable CRLM

Inclusion Criteria:

1. The patient or their legal representative understands and signs the informed consent form.
2. Patients with pMMR/MSS colorectal adenocarcinoma.
3. Aged 18-75 years.
4. Patients with histologically or cytologically confirmed colorectal cancer liver metastases. There must be at least one injectable lesion in the liver, which must also meet the criteria for a measurable target lesion according to RECIST version 1.1 (≥10 mm in the longest diameter on spiral CT/MRI scan with a slice thickness of no greater than 5 mm).
5. Patients with definitively unresectable metachronous liver metastases; OR patients deemed surgically resectable but who refuse surgery, provided the liver metastases meet the following requirements: ① The number of metastatic lesions must be no more than 5, and the sum of the longest diameters of all metastatic lesions must be ≤100 mm; ② The longest diameter of a single lesion must be ≤100 mm; ③ The longest diameter of the lesion to be injected must be ≥10 mm and ≤80 mm.
6. The liver metastases have not received prior radiotherapy, OR the area of the liver near the planned radiotherapy site has not been previously irradiated. At least 700 cc of liver volume must be preserved outside the treatment area.
7. Prior treatments such as hepatic resection, systemic chemotherapy, local ablation therapy, or hepatic artery infusion pump chemotherapy are allowed, provided a washout period of 2 weeks is observed. Patients must have recovered from prior anti-tumor therapy-related adverse events to baseline or Grade ≤1 (according to CTCAE version 5.0) (excluding alopecia and Grade 2 anemia).
8. Child-Pugh score A or B
9. ECOG Performance Status 0-1
10. Peripheral blood counts and liver/renal function within the allowable ranges (tested within 15 days before treatment initiation)
11. No prior history of other concomitant malignancies. Patients must not be pregnant or breastfeeding and should use effective contraception during the study and for 6 months after the last dose.
12. Life expectancy ≥6 months.

Exclusion Criteria:

1. Synchronous colorectal cancer liver metastases.
2. Active hepatitis, cirrhosis, or Child-Pugh class C.
3. Extralepatic metastases to: central nervous system / bone marrow / brain (UICC 8th edition).
4. Liver metastases not measurable.
5. Prior history of oncolytic virus therapy (e.g., T-VEC).
6. Liver metastases not meeting the requirements for peritumoral injection volume or unsuitable for peritumoral injection.
7. History of severe drug allergy (e.g., to oncolytic adenovirus, PD-1 monoclonal antibody, platinum agents, 5-FU, leucovorin, 5-HT3 receptor antagonists, bevacizumab, etc.).
8. Antiviral therapy (e.g., acyclovir, ganciclovir, valacyclovir, vidarabine) within 4 weeks prior to the first dose of study treatment.
9. Participation in another clinical trial within 4 weeks or ongoing participation.
10. History of prior therapy targeting PD-1, PD-L1, PD-L2, CTLA-4, or any other T-cell co-stimulation or checkpoint pathway.
11. Severe electrolyte abnormalities.
12. Significant portal hypertension: history of upper gastrointestinal bleeding or severe hypersplenism.
13. Arterial or deep venous thrombosis within the past 6 months; history or evidence of bleeding tendency within the past 2 months.
14. Pregnant or breastfeeding women, or women with a positive pregnancy test before the first dose; or female participants and their partners unwilling to use strict contraception during the study.
15. Active autoimmune disease requiring systemic treatment (e.g., immunomodulators, corticosteroids, immunosuppressants) within the past 2 years.
16. Past or current other active malignancies (except malignancies cured \>3 years ago or carcinoma in situ treated curatively).
17. Severe ECG abnormalities; active coronary artery disease, severe/unstable angina, newly diagnosed angina, or myocardial infarction within 12 months; New York Heart Association (NYHA) class II or higher congestive heart failure.
18. Active infection (with fever \>38°C).
19. Poorly controlled hypercalcemia, hypertension, or diabetes.
20. Severe pulmonary disease (interstitial pneumonia, pulmonary fibrosis, severe emphysema, etc.).
21. Psychiatric disorder affecting clinical treatment or history of central nervous system disease.
22. Severe complications (intestinal obstruction, renal insufficiency, hepatic insufficiency, cerebrovascular disorders, etc.).
23. Persistent toxicity ≥ Grade 2 (CTCAE v5.0) from prior therapy (except anemia, alopecia, skin pigmentation).
24. Use of any other investigational drug or participation in another interventional trial within 14 days prior to study treatment.
25. Pregnant, breastfeeding, or planning pregnancy during the study; men or women unwilling to use effective contraception.
26. Any unstable medical condition that may affect patient safety or compliance, as judged by the investigator to be unsuitable for the trial.