Allogeneic NK Cell Therapy Combined With Standard Maintenance Treatment in Advanced Solid Tumors

An Exploratory Clinical Study to Evaluate the Safety and Efficacy of Allogeneic NK Cell Injection Combined With Standard Maintenance Therapy in Subjects With Locally Advanced or Metastatic Solid Tumors

This is a prospective, open-label, exploratory clinical study to evaluate the safety and preliminary efficacy of allogeneic natural killer (NK) cell injection combined with standard maintenance therapy in patients with locally advanced or metastatic solid tumors. The study consists of 5 cohorts: Cohort 1 (advanced non-squamous NSCLC with NK cells + PD-(L)1 inhibitor + pemetrexed), Cohort 2 (advanced colorectal adenocarcinoma with NK cells + cetuximab/bevacizumab + capecitabine), Cohort 3 (lymphodepletion exploration cohort with fludarabine + cyclophosph preconditioning followed by NK cells + PD-(L)1 inhibitor + pemetrexed), Cohort 4 (advanced HCC with NK cells + VEGF + PD-(L)1), and Cohort 5 (advanced GC with NK cells + PD-(L)1 + S-1).

This study is designed as a prospective cohort study to evaluate the safety and efficacy of allogeneic NK cell injection combined with standard maintenance therapy in advanced solid tumor patients.

Study Design:

Cohort 1: Advanced non-squamous non-small cell lung cancer (NSCLC) without driver gene mutations, receiving NK cells + PD-(L)1 inhibitor + pemetrexed as first-line maintenance therapy (3-week cycles) Cohort 2: Advanced colorectal adenocarcinoma, receiving NK cells + cetuximab/bevacizumab + capecitabine as first-line maintenance therapy (2-week cycles) Cohort 3: Lymphodepletion exploration cohort for advanced non-squamous NSCLC, receiving fludarabine + cyclophosphamide preconditioning followed by NK cells + PD-(L)1 inhibitor + pemetrexed (3-week cycles) Each cohort includes a safety lead-in phase (3 patients) followed by an expansion phase (3-6 patients). Dose-limiting toxicity (DLT) will be assessed during the first cycle.

Cohort 4 :advanced HCC with NK cells + VEGF + PD-(L)1 (3-week cycles). Cohort 5 :advanced GC with NK cells + PD-(L)1 + S-1 (2-week cycles).

Inclusion Criteria:

1. Age 18-75 years, either gender

2. Subjects must meet one of the following conditions:

   Cohort 1, Cohort 3:

   • Histologically/cytologically confirmed locally advanced unresectable or metastatic non-squamous non-small cell lung cancer (Stage IIIB~IV), without known drug-targetable driver mutations (including but not limited to: EGFR sensitive mutations, ALK gene rearrangements, ROS1 mutations, BRAF 600E mutations, KRAS mutations);
   • Previously received 4~6 cycles of first-line induction therapy with PD-(L)1 combined with pemetrexed and platinum (cycles not combined with chemotherapy are not counted as combined treatment cycles), and imaging assessment shows non-progressive disease (i.e., CR, PR, or SD per RECIST 1.1).

3. Cohort 2:

   • Histologically/cytologically confirmed locally advanced unresectable or metastatic (unresectable Stage III or Stage IV per AJCC 8th Edition) colorectal adenocarcinoma;
   • Previously received 6~9 cycles of first-line induction therapy with cetuximab/bevacizumab combined with FOLFOX/FOLFIRI (cycles not combined with chemotherapy are not counted as combined treatment cycles), and imaging assessment shows non-progressive disease (i.e., CR, PR, or SD per RECIST 1.1).

4. Cohort 4:

   • Histologically/cytologically or clinically diagnosed (by dynamic enhanced MRI/dynamic enhanced CT scan, etc.) locally advanced unresectable or metastatic hepatocellular carcinoma;
   • Barcelona Clinic Liver Cancer (BCLC) Stage C or Stage B (not suitable for surgery/locoregional therapy, including ablation, intervention, and radiotherapy);
   • Child-Pugh score ≤ 7 (Child-Pugh A/B), with no history of hepatic encephalopathy;
   • No prior systemic anti-tumor therapy for HCC;
   • According to RECIST 1.1, at least one measurable lesion exists: non-lymph node lesion long diameter ≥ 1.0 cm, or lymph node lesion short diameter ≥ 1.5 cm; lesions that have received locoregional therapy (e.g., radiotherapy or interventional therapy) cannot be considered target lesions unless there is imaging evidence confirming definite progression of the lesion.

5. Cohort 5:

   • Pathologically histologically or cytologically diagnosed locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma, with HER2 low or negative expression;
   • Previously received 6~9 cycles of first-line induction therapy with PD-(L)1 combined with oxaliplatin and fluoropyrimidine-based chemotherapy (cycles not combined with chemotherapy are not counted as combined treatment cycles), and imaging assessment shows non-progressive disease (i.e., CR, PR, or SD per RECIST 1.1).

6. Prior neoadjuvant/adjuvant chemotherapy is permitted, provided that disease recurrence or metastasis occurs more than 6 months after the last dose of chemotherapy

7. Adequate bone marrow and organ function:

   1. ANC ≥1.5×10⁹/L; Platelet >90×10⁹/L; Hemoglobin >9 g/dL
   2. Liver function: Total bilirubin <1.5×ULN; ALT and AST <3×ULN (<5×ULN if liver metastases present)
   3. Renal function: Serum creatinine ≤1.5×ULN
   4. Coagulation: PT, APTT, INR <1.5×ULN

8. ECOG performance status 0-1

9. Life expectancy ≥3 months

10. Non-pregnant, non-lactating; women of childbearing potential must have negative serum pregnancy test within 7 days before cell infusion and agree to use reliable contraception during study and for 6 months after last infusion; men with partners of childbearing potential must agree to use reliable contraception

11. Voluntary informed consent and able to comply with follow-up

Exclusion Criteria:

1. Prior treatment with other cellular therapy products (DC, CIK, T cells, NK cells, CAR-T, etc.) except this product
2. Other malignancies within 5 years before screening (completely resolved carcinoma in situ and slowly progressing malignancies as determined by investigator excluded)
3. Symptomatic moderate to severe third-space effusion requiring therapeutic drainage
4. Gastrointestinal perforation, fistula, or intra-abdominal abscess within 6 months
5. As assessed by the investigator, intrahepatic tumor mass occupies more than 50% of the entire liver, or tumor thrombus invades major blood vessels (such as the main portal vein, superior mesenteric vein, or inferior vena cava), leading to complications such as portal hypertension or related clinical risks.
6. Significant cardiovascular disease history including
7. Arterial or venous thrombotic events within 6 months before enrollment (CVA, DVT, PE, etc.)
8. Active infection (viral, bacterial, fungal) currently being treated, or any infection requiring IV antibiotics for ≥7 days within past 6 weeks, or oral antibiotics within past 1 week
9. Active autoimmune disease or history of severe autoimmune disease requiring long-term immunosuppression
10. Participation in other interventional clinical trials within 3 months
11. Toxicities from prior interventions not resolved to Grade ≤2 (alopecia excluded)
12. Untreated chronic active hepatitis B, chronic HBV carriers with HBV DNA ≥1000 copies/mL; HCV antibody positive with HCV-RNA positive; HIV antibody positive; syphilis antibody positive
13. Any other condition deemed by investigator to make subject unsuitable for study participation