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

A Randomized, Multicenter, Open-label, Phase II Study of Platinum-Containing Chemotherapy and Sintilimab With or Without Autologous Cytokine-induced Killer Cell Immunotherapy in Stage IV Non-Small Cell Lung Cancer Subjects

This prospective, multi-center, open-label, phase II, randomized controlled trial (CCICC-002b) is to evaluate the efficacy and safety of autologous cytokine-induced killer cell immunotherapy in combination with PD-1 inhibitor and platinum-containing chemotherapy in the first-line treatment of stage IV non-small cell lung cancer (NSCLC).

Inclusion Criteria:

1. Signed written informed consent prior to any trial-related procedures.

2. Age ≥18 and ≤75 years.

3. Histologically or cytologically confirmed stage IV NSCLC (IASLC/UICC 8th edition TNM staging) with no prior systemic therapy for advanced disease.

4. For enrolled adenocarcinoma patients: Absence of EGFR-sensitive mutations and ALK gene fusion alterations confirmed by histological specimens.

5. At least one radiologically measurable lesion per RECIST v1.1. Lesions within prior radiotherapy fields may be considered measurable if progression is confirmed.

6. 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.

7. Asymptomatic or stable brain metastases after local treatment are permitted if all criteria are met:

   1. Measurable extracranial lesions
   2. No CNS symptoms or symptom stability for ≥2 weeks
   3. No corticosteroids required, OR discontinued corticosteroids ≥7 days before first dose, OR stable corticosteroid dose ≤10 mg/day prednisone equivalent for ≥7 days.

8. 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).

9. ECOG performance status 0-1.

10. Life expectancy >3 months.

11. Adequate organ function meeting all laboratory criteria:

    1. Absolute neutrophil count (ANC) ≥1.5×10⁹/L without granulocyte colony-stimulating factor support within 14 days.
    2. Platelets ≥100×10⁹/L without transfusion within 14 days.
    3. Hemoglobin >9 g/dL without transfusion or erythropoietin within 14 days.
    4. Total bilirubin ≤1.5×ULN.
    5. AST/ALT ≤2.5×ULN (≤5×ULN if liver metastases present).
    6. Serum creatinine ≤1.5×ULN AND creatinine clearance (Cockcroft-Gault formula) ≥60 mL/min.
    7. INR/PT ≤1.5×ULN.
    8. Normal thyroid function (TSH within normal range). Subjects with baseline TSH outside normal range may enroll if FT3/FT4 are normal.
    9. Normal myocardial enzyme profile.

12. 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.

13. 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:

1. Pathologically confirmed small cell lung cancer (SCLC), including mixed SCLC-NSCLC histology.

2. Prior radiotherapy meeting any of the following:

   1. Radiation to ≥30% of bone marrow within 14 days before first dose
   2. 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)
   3. Palliative radiotherapy completed ≤7 days before first dose

3. 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).

4. Current participation in interventional clinical trials or receipt of investigational drugs/devices within 4 weeks before first dose.

5. 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).

6. 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).

7. 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.

8. 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.*

9. Clinically uncontrolled pleural/peritoneal effusion (subjects with stable effusion not requiring drainage or ≥3 days post-drainage may enroll).

10. History of allogeneic organ transplantation (except corneal transplants) or hematopoietic stem cell transplantation.

11. Known hypersensitivity to sintilimab, pemetrexed, nab-paclitaxel, carboplatin, or their excipients.

12. Failure to recover from prior intervention-related toxicities (≤Grade 1 or baseline, excluding alopecia/fatigue) before treatment initiation.

13. Known HIV infection (HIV 1/2 antibody positive).

14. Untreated active hepatitis B (HBsAg-positive with HBV-DNA > upper limit of normal [ULN] at local laboratory).

    *Exceptions:*

    1. HBV-DNA <1000 copies/ml (200 IU/ml) before first dose with ongoing antiviral prophylaxis during chemotherapy
    2. Anti-HBc(+) subjects with HBsAg(-), anti-HBs(-), and undetectable HBV-DNA may enroll without prophylaxis but require close monitoring

15. Active HCV infection (HCV antibody-positive with detectable HCV-RNA).

16. 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.*

17. Pregnancy or lactation.

18. Severe uncontrolled systemic diseases including:

    1. Symptomatic ECG abnormalities (e.g., complete left bundle branch block, ≥Grade 2 AV block, ventricular arrhythmias, atrial fibrillation)
    2. Unstable angina, congestive heart failure (NYHA class ≥2)
    3. Myocardial infarction within 6 months
    4. Poorly controlled hypertension (SBP >140 mmHg/DBP >90 mmHg)
    5. Non-infectious pneumonitis requiring steroids within 1 year or active interstitial lung disease
    6. Active tuberculosis
    7. Uncontrolled active infection requiring systemic therapy
    8. Clinically active diverticulitis, abdominal abscess, gastrointestinal obstruction
    9. Decompensated liver disease (e.g., cirrhosis, active hepatitis)
    10. Poorly controlled diabetes (fasting glucose >10 mmol/L)
    11. Urine protein ≥++ with 24-hour protein >1.0 g
    12. Uncontrolled hypercalcemia (>1.5 mmol/L ionized calcium or corrected serum calcium >ULN)
    13. Non-healing wounds/fractures
    14. Psychiatric disorders impairing protocol compliance

19. Any condition that may interfere with study results, compromise subject safety, or preclude full participation as judged by the investigator.