CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Female aged 18-70 years (inclusive of cut-off values); body weight ≥45 kg.
2. Failed to achieve Complete Response (CR) after completion of at least first-line therapy (i.e., surgery and platinum-based chemotherapy), with abnormal CA125 levels or at least one measurable lesion confirmed by imaging assessment.
3. Completed genomic and transcriptomic sequencing of tumor samples, finished the analysis of genetic mutation characteristics and immune characteristics of tumor samples, and is eligible for screening of personalized tumor neoantigens.
4. Laboratory examinations must meet the following criteria: white blood cell count ≥4.0×10⁹/L; absolute lymphocyte count ≥1.0×10⁹/L; platelet count ≥80×10⁹/L; hemoglobin ≥9.0 g/L; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5×Upper Limit of Normal (ULN) (≤5×ULN for patients with concurrent liver metastases); bilirubin ≤1.5×ULN (≤3×ULN for patients with Gilbert's syndrome); alkaline phosphatase (ALP) ≤2.5×ULN (≤5×ULN for patients with concurrent liver metastases); albumin ≥30 g/L; serum creatinine and/or urea \<1.5 times the normal value; coagulation tests: international normalized ratio (INR) \<1.7 or prolonged prothrombin time (PT) \<4 seconds.
5. 12-lead electrocardiogram (ECG) must meet the following criteria: no severe arrhythmia, QTcF ≤480 ms.
6. Toxic and adverse reactions induced by previous treatments must have recovered to Grade ≤1 (per NCI-CTCAE v5.0), with the exception of stable Grade 2 sensory neuropathy or alopecia (per CTCAE).
7. With patent vascular access and capable of undergoing peripheral blood mononuclear cell (PBMC) collection.
8. Expected survival time \>6 months.
9. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) score of 0-1 (see Appendix 2).
10. Fertile study participants must agree to adopt medically effective contraceptive measures throughout the trial period and for at least 6 months after the last administration; fertile study participants must have a negative pregnancy test result within 28 days prior to enrollment and at baseline.
11. Study participants are able to understand the trial procedures, are willing to comply with the clinical trial protocol to complete the trial, and have signed the informed consent form (ICF).

Exclusion Criteria:

1. (Per interview) Allergic diathesis with hypersensitivity to two or more drugs, or known hypersensitivity to any component of the personalized neoantigen-sensitized autologous dendritic cell injection (cell cryopreservation solution CS10, human albumin, 0.9% sodium chloride injection).
2. (Per interview) A past or current diagnosis of Myelodysplastic Syndrome (MDS) or Acute Myeloid Leukemia (AML).
3. (Per interview) Patients with symptomatic, uncontrolled brain metastasis or leptomeningeal metastasis.
4. (Per interview) Suffering from severe or uncontrolled diseases, including but not limited to: uncontrolled ventricular arrhythmia, myocardial infarction within the recent 3 months, uncontrolled grand mal epilepsy, unstable spinal cord compression, superior vena cava syndrome, immunodeficiency (excluding splenectomy), or other diseases that the investigator deems may expose the patient to a high risk of harm.
5. Positive for Human Immunodeficiency Virus (HIV) antibody, Treponema Pallidum (TP) antibody, or Hepatitis C Virus (HCV) antibody; or evidence of active hepatitis B via Hepatitis B Virus (HBV) surface antigen/HBV DNA testing.
6. New York Heart Association (NYHA) Grade III-IV congestive heart failure, or clinically significant arrhythmia with poor control.
7. Uncontrolled arterial hypertension (systolic blood pressure ≥160 mmHg or diastolic blood pressure ≥100 mmHg).
8. (Per interview) A history of or current comorbidities including the following:a) Autoimmune disease requiring long-term (more than 2 months) systemic immunosuppressant (corticosteroid) therapy, or immune-mediated symptomatic diseases (including ulcerative colitis, Crohn's disease, rheumatoid arthritis, Systemic Lupus Erythematosus (SLE), autoimmune vasculitis (e.g., Wegener's granulomatosis));b) A past diagnosis of immune-mediated motor neuron disease;c) A past diagnosis of Toxic Epidermal Necrolysis (TEN);d) Any psychiatric disorder (including dementia, altered mental status) that may impair the understanding and completion of informed consent and relevant questionnaires;e) Long-term use of non-inhaled corticosteroids, hydroxyurea, or immunomodulatory drugs;f) A history of other active malignant tumors within the past 5 years (excluding patients with basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the breast that have been completely cured and require no follow-up treatment);g) Hypothyroidism (patients with hypothyroidism requiring only thyroid hormone replacement therapy are eligible for enrollment).
9. (Per interview) Judged by the investigator as unsuitable for enrollment or unable to comply with the protocol requirements, including but not limited to: persistent fever (\>24 h) documented by repeated measurements or due to active, uncontrolled infection from screening to prior to drug administration.
10. (Per interview) Receipt of cellular immunotherapy within the past 6 months (including: Cytokine-Induced Killer (CIK) cells, dendritic cell (DC) therapy, DC-CIK therapy, Lymphokine-Activated Killer (LAK) cells, and other cellular immunotherapies).

    In addition to the above requirements, patients who meet any of the following criteria shall also be excluded prior to the collection of autologous peripheral blood mononuclear cells (PBMCs):
11. Receipt of platelet or red blood cell transfusion within 3 weeks prior to collection.
12. Receipt of chemotherapy within 3 weeks prior to collection.
13. Receipt of anti-angiogenic tyrosine kinase inhibitor (TKI) small-molecule drugs within 3 weeks prior to collection.
14. Use of corticosteroids (or analogs) or systemic administration of immunomodulatory therapies within 3 weeks prior to collection.
15. Participation in a clinical study of an investigational non-biolgical product (administered within the past 30 days or 5 half-lives, whichever is longer) or an investigational biological product (monoclonal or polyclonal antibodies) (administered within the past 4 months or 5 half-lives, whichever is longer) prior to screening.
16. Pregnant or lactating female study participants.
17. Study participants with insufficient sensitivity to immunotherapy as determined by tumor genetic analysis.
18. Study participants who are judged by the investigator as unable to adhere to the trial procedures, or deemed ineligible for enrollment for any other reason.

主要终点：Evaluate the safety and tolerability of YS247 in study participants with HRD-negative epithelial ovarian cancer, and to determine the Maximum Tolerated Dose (MTD) / Recommended Expansion Dose. · 12 months

• Adhering to the 3+3 dose escalation principle, a dose escalation design will be adopted · EXPERIMENTAL · Adhering to the 3+3 dose escalation principle, a dose escalation design will be adopted. Three dose levels (low, medium, and high) are preset for the injection dose of the investigational product YS247, with 3 to 6 study subjects planned to be enrolled in each dose cohort. An adaptive trial design will be implemented, and the number of enrolled subjects in each cohort will be adjusted based on the actual results of the clinical study。 Each study subject will receive a total of 8 treatment cycles (8 administrations). For each administration, YS247 may be delivered via a maximum of 3 injection sites, with a maximum volume of 0.3 mL of YS247 injected per site.

This is a single-center, open-label, dose-escalation, multiple-dose investigator-initiated exploratory study designed to evaluate the safety, tolerability and preliminary efficacy of tumor neoantigen-pulsed autologous dendritic cell injection (YS247) in participants with HRD-negative epithelial ovarian cancer.