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

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.

Inclusion criteria

• Age 18-75 years, either gender
• Cohort 1 & 3: Histologically or cytologically confirmed locally advanced unresectable or metastatic non-squamous NSCLC (Stage IIIB-IV) without known actionable driver gene mutations (including but not limited to: EGFR sensitizing mutations, ALK rearrangement, ROS1 rearrangement, BRAF V600E mutation, KRAS mutation)
• Cohort 1 & 3: Previously received 4-6 cycles of first-line induction therapy with PD-(L)1 inhibitor combined with pemetrexed plus platinum, with radiographic assessment of non-progressive disease (CR, PR, or SD per RECIST 1.1)
• Cohort 2: Histologically or cytologically confirmed locally advanced unresectable or metastatic colorectal adenocarcinoma (unresectable Stage III or Stage IV per AJCC 8th edition)
• Cohort 2: Previously received 6-9 cycles of first-line induction therapy with cetuximab or bevacizumab combined with FOLFOX or FOLFIRI, with radiographic assessment of non-progressive disease (CR, PR, or SD per RECIST 1.1)
• Prior neoadjuvant/adjuvant chemotherapy allowed if disease recurrence or metastasis occurred >6 months after last chemotherapy dose
• At least one measurable lesion per RECIST 1.1 (except patients who achieved CR during induction therapy): non-lymph node lesion ≥1.0 cm in longest diameter, or lymph node lesion ≥1.5 cm in short diameter; lesions treated with local therapy (radiation or interventional) cannot be target lesions unless progression is documented
• Adequate bone marrow and organ function:

• ANC ≥1.5×10⁹/L; Platelet >90×10⁹/L; Hemoglobin >9 g/dL
• Liver function: Total bilirubin <1.5×ULN; ALT and AST <3×ULN (<5×ULN if liver metastases present)
• Renal function: Serum creatinine ≤1.5×ULN
• Coagulation: PT, APTT, INR <1.5×ULN
• ECOG performance status 0-1
• Life expectancy ≥3 months
• 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
• Voluntary informed consent and able to comply with follow-up

Exclusion criteria

• Prior treatment with other cellular therapy products (DC, CIK, T cells, NK cells, CAR-T, etc.) except this product
• Other malignancies within 5 years before screening (completely resolved carcinoma in situ and slowly progressing malignancies as determined by investigator excluded)
• Symptomatic moderate to severe third-space effusion requiring therapeutic drainage
• Gastrointestinal perforation, fistula, or intra-abdominal abscess within 6 months
• Significant cardiovascular disease history including
• Arterial or venous thrombotic events within 6 months before enrollment (CVA, DVT, PE, etc.)
• 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
• Active autoimmune disease or history of severe autoimmune disease requiring long-term immunosuppression
• Participation in other interventional clinical trials within 3 months
• Toxicities from prior interventions not resolved to Grade ≤2 (alopecia excluded)
• 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
• Any other condition deemed by investigator to make subject unsuitable for study participation