Hepatic-artery NKG2D CAR-NK followed by IV NKG2D CAR-T for advanced solid tumors with liver metastases

Hepatic Artery Transfusion of NKG2D CAR-NK Cells Followed by Intravenous Infusion of NKG2D CAR-T Cells to Treat Patients With Advanced Solid Tumors With Liver Metastases Who Have Failed Standard Treatments: a Phase I Exploratory Clinical Trial

This treatment will try a two-step approach—hepatic artery infusion of NKG2D CAR-NK cells followed by intravenous NKG2D CAR-T cells—for people with advanced solid tumors that have spread to the liver and did not respond to standard treatments.

Quick facts

• Phase: Phase 1
• Study type: Interventional
• Enrollment: 12 (estimated)
• Ages: 18 Years to 75 Years
• Sex: All
• Sponsor: Zhejiang University (Academic / other)
• Drugs / interventions: bevacizumab, cetuximab, fruquintinib, prednisone, CAR-T, immunotherapy
• Locations: 1 site (Hangzhou, Zhejiang)
• Trial ID: NCT07021534 on ClinicalTrials.gov

What this trial studies

This is a single-center, single-arm, open-label dose-escalation Phase I trial enrolling about 9–18 patients with advanced solid tumors and liver metastases who have failed standard therapies. Participants receive a fixed hepatic artery infusion of NKG2D CAR-NK cells delivered over two days via an indwelling catheter, followed 1–2 weeks later by two consecutive intravenous infusions of NKG2D CAR-T cells with classical 3+3 dose escalation starting at 1.5×10^7 cells/kg. The primary goals are to determine the maximum tolerated dose and recommended Phase II dose while systematically monitoring treatment-emergent adverse events and cellular kinetics. Secondary objectives include pharmacokinetic and pharmacodynamic profiling, correlative biomarker analyses, and initial measures of antitumor activity by RECIST criteria.

Who should consider this trial

Good fit: Adults aged 18–75 with advanced solid tumors and measurable liver metastases who have failed standard treatments, have an expected survival ≥12 weeks, and preferably show high expression of NKG2D ligands are the intended candidates.

Not a fit: Patients with poor performance status, very short expected survival, uncontrolled comorbidities or infections, or tumors with low or absent NKG2D ligand expression are unlikely to benefit from this intervention.

Why it matters

Potential benefit: If successful, this approach could reduce liver tumor burden and extend disease control for patients who have exhausted approved treatments.

How similar studies have performed: Early-phase CAR-NK and CAR-T studies have shown acceptable safety and occasional signals of activity, but the specific sequence of hepatic-artery NKG2D CAR-NK followed by systemic NKG2D CAR-T is largely novel and not yet proven.

Eligibility criteria

Inclusion Criteria:

1. Age between 18 and 75 years (inclusive of boundary values), both males and females are eligible.
2. Advanced solid tumors with liver metastasis that have failed prior standard treatment (including disease progression and intolerable adverse reactions). The colorectal cancer cohort will be enrolled first (prior standard treatment includes combination or sequential therapy with fluorouracil, oxaliplatin, and irinotecan, with or without bevacizumab and/or cetuximab and/or regorafenib and/or fruquintinib).
3. Patients with high expression of NKG2D ligands in tumor tissue sections will be prioritized for enrollment.
4. The expected survival of the subjects is ≥12 weeks.
5. Subjects must have at least one target lesion that can be stably assessed according to the RECIST v.1.1 criteria by CT, MRI, or PET-CT. The target lesion should have measurable dimensions (tumor lesion long diameter ≥10 mm on CT scan, lymph node lesion short diameter ≥15 mm on CT scan, and scan slice thickness no more than 5 mm). Alternatively, through laparoscopic exploration, there should be at least one target lesion that can be assessed according to the PCI scoring criteria.
6. Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0-1.
7. Subjects must have adequate organ and bone marrow function. Laboratory screening must meet all of the following criteria, with all laboratory test results within the specified stable range and without ongoing supportive therapy.

   1. Hematology: White blood cell count (WBC) ≥1.5×10⁹/L; platelet count (PLT) ≥60×10⁹/L; hemoglobin (Hb) ≥8.0 g/dL; lymphocyte count (LYM) ≥0.4×10⁹/L.
   2. Biochemistry: Serum creatinine ≤1.5×ULN. If serum creatinine \>1.5×ULN, creatinine clearance rate must be \>50 mL/min (calculated by the Cockcroft-Gault formula); serum total bilirubin ≤1.5×ULN; alanine aminotransferase (ALT) ≤2×ULN; aspartate aminotransferase (AST) ≤2×ULN (for patients with liver metastasis or primary liver cancer, ALT ≤5×ULN and AST ≤5×ULN); amylase and lipase ≤1.5×ULN.
   3. Urinalysis: Urine protein \<2+.
8. Echocardiogram within the past month showing left ventricular ejection fraction (LVEF) \>45%.
9. Fertility status: Women of childbearing potential or men whose sexual partners are women of childbearing potential must agree to use effective contraception from the time of signing the informed consent form until 6 months after the last cell infusion (women of childbearing potential include premenopausal women and women within 2 years after menopause).
10. Subjects must sign a written informed consent form and date it.
11. Subjects must be willing and able to comply with the prescribed treatment plan, laboratory tests, follow-up visits, and other study requirements.

Exclusion Criteria:

1. Pregnant or breastfeeding women.
2. Known history of human immunodeficiency virus (HIV) infection; acute or chronic active hepatitis B (HBsAg positive); acute or chronic active hepatitis C (HCV antibody positive). Positive syphilis antibody; EB virus DNA quantitative \>500 copies; cytomegalovirus (CMV) infection (IgM positive).
3. Active or poorly controlled severe infections.
4. Presence of severe arterial embolism identified by CT angiography or hepatic arterial vascular variations that are unfavorable for HAI treatment.
5. Current presence of cardiac disease requiring treatment or poorly controlled hypertension as judged by the investigator (defined as systolic blood pressure ≥140 mmHg and/or diastolic blood pressure \>90 mmHg after standardized antihypertensive drug treatment).
6. Presence of any of the following cardiac clinical symptoms or diseases:

   1. Unstable angina.
   2. Myocardial infarction within the past year.
   3. Resting electrocardiogram (ECG) showing QTc \>450 ms (male) or QTc \>470 ms (female).
   4. Resting ECG revealing clinically significant abnormalities (such as abnormal heart rate, conduction, or morphological features) or complete left bundle branch block or third-degree heart block or second-degree heart block or PR interval \>250 ms.
   5. Presence of factors that increase the risk of QTc prolongation or arrhythmias, such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or sudden unexplained death in first-degree relatives under the age of 40, or use of drugs that prolong the QT interval.
7. Coagulation abnormalities (INR \>1.5×ULN), tendency to bleed, or undergoing thrombolytic or routine anticoagulant therapy (e.g., warfarin or heparin). Patients requiring long-term antiplatelet therapy (aspirin, dose \>300 mg/day; clopidogrel, dose \>75 mg/day).
8. Subjects who require systemic treatment with corticosteroids or other immunosuppressive drugs during the treatment period.
9. Oxygen saturation ≤95% (measured by pulse oximetry) before treatment.
10. Systemic corticosteroid use equivalent to \>15 mg/day prednisone within 4 weeks before treatment (excluding inhaled corticosteroids).
11. Development of new arrhythmias in the subject before lymphodepletion conditioning, including but not limited to uncontrolled arrhythmias with medication, hypotension requiring vasopressors, bacterial, fungal, or viral infections requiring intravenous antibiotics. Subjects receiving prophylactic antibiotics for infection will be assessed by the investigator for continued eligibility.
12. Known history of or current need for treatment of hepatic encephalopathy; subjects with current or history of central nervous system disorders, such as seizures, cerebral ischemia/infarction, dementia, cerebellar disease, or any autoimmune diseases involving the central nervous system; subjects with clinically symptomatic central nervous system metastases or leptomeningeal metastases, or other evidence indicating that the central nervous system metastases or leptomeningeal metastases are not controlled, and deemed unsuitable for enrollment by the investigator.
13. Subjects with previous or concurrent other malignancies, with the following exceptions: a) Adequately treated basal cell or squamous cell carcinoma (with sufficient wound healing required before enrollment in the study). b) Cervical carcinoma in situ or ductal carcinoma in situ of the breast, treated with curative intent, with no signs of recurrence for at least 3 years before the study. c) Primary malignancy that has been completely resected and in complete remission for ≥5 years.
14. Subjects with severe psychiatric disorders.
15. Participation in another clinical study within the past month.
16. Subjects assessed by the investigator as unable or unwilling to comply with the requirements of the study protocol.
17. Subjects who have withdrawn from the study for any reason and cannot re-enroll.

Where this trial is running

Hangzhou, Zhejiang

• The First Affiliated Hospital Zhejiang University School of Medicine — Hangzhou, Zhejiang, China (Recruiting)

Study contacts

• Study coordinator: Weijia Fang

Conditions Patients With Advanced Solid Tumors With Liver Metastases Who Have Failed Standard Treatments; NKG2D CAR-NK, NKG2D CAR-T, Solid Tumor; liver metastases