Safety and tolerability of NEUK203-13 CAR-NK cells for DLL3 in advanced neuroendocrine tumors

Inclusion Criteria:

* 1\. Understand and voluntarily sign the Informed Consent Form (ICF);
* 2\. Aged ≥ 18 years and \< 75 years at the time of signing the ICF, regardless of gender;
* 3\. Pathologically confirmed neuroendocrine tumors, including small cell lung cancer (SCLC), etc.;
* 4\. Previous failure or intolerance to systemic therapy, or recurrence after remission: among them, patients with small cell lung cancer must have received at least platinum-based chemotherapy with or without PD-1/PD-L1 inhibitors in previous treatments, with imaging evidence of disease progression after treatment;
* 5\. Must provide tissue samples for biomarker analysis, preferably newly obtained tissues. For patients unable to provide newly obtained tissues, 4 unstained sections of archived formalin-fixed, paraffin-embedded (FFPE) tissues can be provided (at least 1 patient with high DLL3 expression shall be enrolled in each dose group: high expression is defined as positive staining in ≥ 50% of tumor cells; preference is given to enrolling DLL3-positive patients);
* 6\. Have at least one measurable lesion as the target lesion (per RECIST v1.1 criteria);
* 7\. Expected survival ≥ 3 months;
* 8\. Eastern Cooperative Oncology Group (ECOG) performance status score of 0-1;
* 9\. Have adequate bone marrow reserve and organ function within 7 days before the first administration of NEUK203-13 Injection:
* 10\. Sufficient bone marrow function (no supportive therapy within 14 days before the first administration): hemoglobin (Hb) ≥ 90 g/L, platelets (PLT) ≥ 75 × 10⁹/L, absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L;
* 11\. Liver function: aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper limit of normal (ULN), total bilirubin (TBIL) \< 1.5 × ULN;
* 12\. Renal function: serum creatinine (Scr) ≤ 1.5 × ULN and creatinine clearance rate (Ccr) ≥ 60 mL/min (calculated according to the Cockcroft-Gault formula); Coagulation function: prothrombin time (PT) ≤ 1.5 × ULN, international normalized ratio (INR) ≤ 2.0;
* 13\. Female patients of childbearing potential or male patients whose partners are of childbearing potential agree to use highly effective contraceptive measures from any dose administration in the study until 6 months after the last dose of the study.

Exclusion Criteria:

* 1\. Mixed carcinoma with non-neuroendocrine tumor components;
* 2\. Active brain metastases (patients with stable disease for 3 months after treatment without the need for continued glucocorticoid therapy are eligible for enrollment); known leptomeningeal metastases; isolated central nervous system (CNS) disease progression without evidence of progression outside the CNS;
* 3\. A history of hypersensitivity to interleukin-2 (IL-2), fludarabine, cyclophosphamide, tocilizumab, or any component of the infusion product formulation; or patients with a history of specific allergic disorders (asthma, rubella, eczematous dermatitis);
* 4\. Prior receipt of any of the following treatments:
* 5\. Any systemic antineoplastic therapy within 4 weeks or 5 half-lives prior to the first administration of NEUK203-13 Injection, whichever is shorter;
* 6\. Radiotherapy not involving the thoracic cavity within 2 weeks prior to the first administration of NEUK203-13 Injection, or radiotherapy involving the thoracic cavity within 4 weeks prior to the first administration of the study drug, whichever is longer;
* 7\. Concurrent enrollment in another clinical study, unless it is an observational (non-interventional) clinical study;
* 8\. Prior vaccination with an antineoplastic vaccine, or receipt of a live vaccine within 4 weeks prior to the first administration of NEUK203-13 Injection;
* 9\. Major surgery or severe trauma within 4 weeks prior to the first administration of NEUK203-13 Injection;
* 10\. Failure of toxicities from prior antineoplastic therapy to resolve to ≤ Grade 1 according to the Common Terminology Criteria for Adverse Events (CTCAE) (except alopecia) or to the level specified in the inclusion/exclusion criteria, whichever is more stringent;
* 11\. Active autoimmune disease or a history of autoimmune disease (e.g., interstitial pneumonia, colitis, hepatitis, hypophysitis, vasculitis, nephritis, hyperthyroidism, hypothyroidism, including but not limited to these diseases or syndromes); exceptions include patients with vitiligo, patients with a history of childhood asthma/allergies that have resolved completely and require no intervention in adulthood, patients with autoimmune-mediated hypothyroidism receiving a stable dose of thyroid replacement hormone, and patients with type 1 diabetes receiving a stable dose of insulin;
* 12\. A history of immunodeficiency, including positive HIV test results, or other acquired or congenital immunodeficiency diseases, or a history of organ transplantation or allogeneic bone marrow transplantation;
* 13\. Severe infection (CTCAE \> Grade 2) within 4 weeks prior to the first administration of NEUK203-13 Injection, such as severe pneumonia requiring hospitalization, bacteremia, infectious complications, etc.; baseline chest imaging indicating active pulmonary inflammation; or presence of signs and symptoms of infection requiring oral or intravenous antibiotic therapy within 2 weeks prior to the first administration of the study drug (except for prophylactic antibiotic use);
* 14\. Tuberculosis infection identified by medical history or CT examination; Active hepatitis B (HBV DNA ≥ 500 IU/mL), hepatitis C (positive anti-HCV antibodies and HCV-RNA above the lower limit of detection of the assay), or positive syphilis test results (including positive RPR or TPPA);
* 15\. Prior diagnosis of any other malignant tumor, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical or breast cancer, or adequately treated localized prostate cancer;
* 16\. Pregnant or lactating women;
* 17\. Uncontrolled concurrent diseases, including but not limited to: documented cerebrovascular events (stroke or transient ischemic attack) within 6 months prior to the first administration of the study drug, symptomatic congestive heart failure, left ventricular ejection fraction (LVEF) \< 50%, uncontrolled hypertension, unstable angina pectoris, uncontrolled arrhythmias, severe chronic gastrointestinal disease with diarrhea, or severe dyspnea requiring oxygen therapy;
* 18\. A definite history of neurological or psychiatric disorders that, in the investigator's judgment, may affect the patient's cognitive function or compliance, including unstable epilepsy, dementia, schizophrenia, etc.; or psychiatric illnesses/social conditions that may affect study compliance, significantly increase the risk of adverse events, or impair the patient's ability to provide written informed consent;
* 19\. Other factors judged by the investigator that may force the patient to terminate the study prematurely, such as severely abnormal laboratory test results, and/or family or social factors that may affect patient safety or the collection of trial data.