Phase II Study of Chemotherapy and PD-1 Inhibitor Combination With Autologous CIK Cell Immunotherapy to Treat Lung Cancer

Inclusion criteria

• Signed written informed consent prior to any trial-related procedures.
• Age ≥18 and ≤75 years.
• Histologically or cytologically confirmed stage IV NSCLC (IASLC/UICC 8th edition TNM staging) with no prior systemic therapy for advanced disease.
• For enrolled adenocarcinoma patients: Absence of EGFR-sensitive mutations and ALK gene fusion alterations confirmed by histological specimens.
• At least one radiologically measurable lesion per RECIST v1.1. Lesions within prior radiotherapy fields may be considered measurable if progression is confirmed.
• No prior systemic antitumor therapy for advanced/metastatic disease. Subjects who received:

• Platinum-based adjuvant/neoadjuvant chemotherapy, or
• Definitive chemoradiotherapy for limited-stage disease are eligible if disease progression/recurrence occurred ≥6 months after last chemotherapy.
• Asymptomatic or stable brain metastases after local treatment are permitted if all criteria are met:

• Measurable extracranial lesions
• No CNS symptoms or symptom stability for ≥2 weeks
• No corticosteroids required, OR discontinued corticosteroids ≥7 days before first dose, OR stable corticosteroid dose ≤10 mg/day prednisone equivalent for ≥7 days.
• Palliative radiotherapy (including brain RT for symptomatic metastases) is allowed if completed ≥1 week before first dose and radiation-related toxicities have recovered to ≤Grade 1 (CTCAE v5.0, excluding alopecia).
• ECOG performance status 0-1.
• Life expectancy >3 months.
• Adequate organ function meeting all laboratory criteria:

• Absolute neutrophil count (ANC) ≥1.5×10⁹/L without granulocyte colony-stimulating factor support within 14 days.
• Platelets ≥100×10⁹/L without transfusion within 14 days.
• Hemoglobin >9 g/dL without transfusion or erythropoietin within 14 days.
• Total bilirubin ≤1.5×ULN.
• AST/ALT ≤2.5×ULN (≤5×ULN if liver metastases present).
• Serum creatinine ≤1.5×ULN AND creatinine clearance (Cockcroft-Gault formula) ≥60 mL/min.
• INR/PT ≤1.5×ULN.
• Normal thyroid function (TSH within normal range). Subjects with baseline TSH outside normal range may enroll if FT3/FT4 are normal.
• Normal myocardial enzyme profile.
• For women of childbearing potential: Negative urine/serum pregnancy test within 3 days prior to first dose (Cycle 1 Day 1). Non-childbearing potential is defined as ≥1 year post-menopause, surgically sterilized, or hysterectomy.
• All subjects (regardless of gender) at risk of conception must use highly effective contraception (failure rate <1% annually) during treatment and for 120 days (or 180 days per protocol) after last dose.

Exclusion criteria

• Pathologically confirmed small cell lung cancer (SCLC), including mixed SCLC-NSCLC histology.
• Prior radiotherapy meeting any of the following:

• Radiation to ≥30% of bone marrow within 14 days before first dose
• Lung radiation >30 Gy within 6 weeks before treatment (subjects must have recovered to ≤Grade 1 toxicity, no corticosteroid requirement, and no history of radiation pneumonitis)
• Palliative radiotherapy completed ≤7 days before first dose
• Diagnosis of malignancies other than NSCLC within 5 years before first dose (except cured basal cell carcinoma, squamous cell carcinoma, or resected carcinoma in situ).
• Current participation in interventional clinical trials or receipt of investigational drugs/devices within 4 weeks before first dose.
• Prior therapy with anti-PD-1/PD-L1/PD-L2 agents or drugs targeting other T-cell co-stimulatory/checkpoint pathways (e.g., CTLA-4, OX-40, CD137).
• Systemic treatment with Chinese herbal medicines (for lung cancer indications) or immunomodulatory agents (e.g., thymosin, interferon, interleukin) within 14 days before first dose (except local pleural control).
• Active autoimmune disease requiring systemic treatment (e.g., disease-modifying agents, corticosteroids, immunosuppressants) within 2 years before first dose. Replacement therapies (e.g., thyroid hormone, insulin, physiologic corticosteroids) are permitted.
• Systemic corticosteroids (>10 mg/day prednisone equivalent) or immunosuppressive therapy within 7 days before first dose (excluding topical/nasal/inhaled corticosteroids).

*Note: Physiologic corticosteroid doses (≤10 mg/day prednisone equivalent) are allowed.*

• Clinically uncontrolled pleural/peritoneal effusion (subjects with stable effusion not requiring drainage or ≥3 days post-drainage may enroll).
• History of allogeneic organ transplantation (except corneal transplants) or hematopoietic stem cell transplantation.
• Known hypersensitivity to sintilimab, pemetrexed, nab-paclitaxel, carboplatin, or their excipients.
• Failure to recover from prior intervention-related toxicities (≤Grade 1 or baseline, excluding alopecia/fatigue) before treatment initiation.
• Known HIV infection (HIV 1/2 antibody positive).
• Untreated active hepatitis B (HBsAg-positive with HBV-DNA > upper limit of normal [ULN] at local laboratory).

*Exceptions:*

• HBV-DNA <1000 copies/ml (200 IU/ml) before first dose with ongoing antiviral prophylaxis during chemotherapy
• Anti-HBc(+) subjects with HBsAg(-), anti-HBs(-), and undetectable HBV-DNA may enroll without prophylaxis but require close monitoring
• Active HCV infection (HCV antibody-positive with detectable HCV-RNA).
• Live vaccination within 30 days before Cycle 1 Day 1. *Note: Inactivated vaccines (e.g., seasonal influenza) are permitted; live attenuated vaccines (e.g., nasal flu vaccine) are prohibited.*
• Pregnancy or lactation.
• Severe uncontrolled systemic diseases including:

• Symptomatic ECG abnormalities (e.g., complete left bundle branch block, ≥Grade 2 AV block, ventricular arrhythmias, atrial fibrillation)
• Unstable angina, congestive heart failure (NYHA class ≥2)
• Myocardial infarction within 6 months
• Poorly controlled hypertension (SBP >140 mmHg/DBP >90 mmHg)
• Non-infectious pneumonitis requiring steroids within 1 year or active interstitial lung disease
• Active tuberculosis
• Uncontrolled active infection requiring systemic therapy
• Clinically active diverticulitis, abdominal abscess, gastrointestinal obstruction
• Decompensated liver disease (e.g., cirrhosis, active hepatitis)
• Poorly controlled diabetes (fasting glucose >10 mmol/L)
• Urine protein ≥++ with 24-hour protein >1.0 g
• Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or corrected serum calcium >ULN)
• Non-healing wounds/fractures
• Psychiatric disorders impairing protocol compliance
• Any condition that may interfere with study results, compromise subject safety, or preclude full participation as judged by the investigator.