CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

1. Age 18-70 years (inclusive) at the time of informed consent; sex unrestricted.
2. Voluntary participation: the subject (or legally authorized representative) must provide written informed consent (ICF, Informed Consent Form).
3. Histologically confirmed advanced gastric or gastroesophageal junction adenocarcinoma that has progressed after ≥ 2 prior systemic regimens, OR histologically confirmed advanced pancreatic adenocarcinoma that has progressed after ≥ 1 prior systemic regimen.
4. CLDN18.2 positivity in archival or fresh tumor tissue by immunohistochemistry (IHC): ≥ 40% of tumor cells staining ≥ 2+.
5. At least one measurable lesion per RECIST 1.1 (longest diameter ≥ 10 mm).
6. Estimated life expectancy \> 12 weeks.
7. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
8. Adequate organ function within 14 days prior to leukapheresis, defined by all of the following:

(1) Total bilirubin ≤ 2 × ULN (Upper Limit of Normal); (2) ALT and AST ≤ 2.5 × ULN (≤ 5 × ULN if liver or bone metastases are present); (3) Calculated creatinine clearance (Cockcroft-Gault) ≥ 50 mL/min; (4) Hemoglobin ≥ 90 g/L; (5) White blood cell (WBC) count ≥ 1.5 × 10⁹/L, with documented suitable venous access for leukapheresis and no contraindications to leukapheresis; (6) Absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L without Granulocyte Colony-Stimulating Factor (G-CSF) or other myeloid growth factors within 7 days of screening labs; (7) Absolute lymphocyte count ≥ 0.5 × 10⁹/L; (8) Platelet count ≥ 80 × 10⁹/L without transfusion within 7 days of screening labs; (9) Prothrombin time (PT) prolongation ≤ 4 s above ULN; (10) Oxygen saturation ≥ 95% on room air. 9: Contraception and pregnancy requirements: Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and again before lymphodepleting chemotherapy; must not be breastfeeding. WOCBP and fertile men must use a highly effective contraceptive method from screening until 12 months after CBG131 infusion or study discontinuation, whichever is later.

Exclusion Criteria:

1. Pregnant or lactating women.
2. Active bacterial or fungal infection within 72 h before lymphodepletion. Subjects receiving prophylactic antibiotics, antifungals or antivirals are allowed if there is no evidence of active infection and the agents are not on the prohibited-medication list.
3. Systemic corticosteroids equivalent to \> 15 mg/day prednisone within 2 weeks before leukapheresis (inhaled or topical steroids permitted). Any systemic glucocorticoids within 7 days before leukapheresis, except inhaled or topical preparations.
4. Live-attenuated vaccine within 4 weeks before leukapheresis or planned during the study.
5. Positive HBsAg or HBcAb with HBV-DNA ≥ ULN; positive HCV antibody with detectable HCV RNA; positive HIV antibody; positive syphilis serology.
6. Prior hypersensitivity to immunotherapy, cyclophosphamide, fludarabine, albumin-bound paclitaxel, tocilizumab, or any component of CBG131 (e.g. DMSO), or other significant allergic history.
7. Anti-cancer therapy within 2 weeks before leukapheresis (or 5 half-lives, whichever is shorter), including surgery, systemic chemotherapy, radiotherapy, interventional procedures, or anti-PD-1/PD-L1 monoclonal antibody (mAb)/Claudin18.2-targeted agents/other investigational drugs within 4 weeks (or 5 half-lives).
8. Prior gene-engineered cellular therapy (e.g. CAR-T, TCR-T, TIL).
9. Major surgery within 4 weeks before leukapheresis or significant trauma, or anticipated major surgery during the study (except cataract or local-anaesthetic procedures).
10. Known or suspected brain metastases.
11. Portal-vein tumor thrombus or tumor thrombus in mesenteric/inferior vena cava on imaging.
12. Central or extensive pulmonary metastases, extensive liver metastases, or widespread bone metastases.
13. History of organ transplantation or on transplant waiting list.
14. Uncontrolled or serious illnesses that could limit participation, including: Diabetes with HbA1c \> 8%, uncontrolled hypertension (\> 160/100 mmHg), Left Ventricular Ejection Fraction (LVEF) \< 50%, congestive heart failure, acute MI, severe arrhythmia, unstable angina within 6 months, pulmonary embolism, COPD, ILD, clinically significant pulmonary-function abnormalities; Active peptic ulcer, active GI bleeding, bleeding diathesis, major GI bleed within 3 months, prior immunotherapy-related bleeding, hypotension requiring vasopressors.
15. Deep ulceration of primary tumor, full-thickness infiltration at anastomotic recurrence, or tumor encasing/invading major vessels on CT/MRI ± endoscopy, carrying high risk of bleeding or perforation.
16. Requirement for warfarin or heparin anticoagulation.
17. Chronic antiplatelet therapy at doses exceeding aspirin 100 mg/day or clopidogrel 75 mg/day.
18. Toxicities from prior therapies not resolved to ≤ Grade 1 or baseline (except alopecia, pigmentation, or laboratory abnormalities allowed by protocol) at informed-consent signature.
19. Clinically significant CNS disease, abnormal neurologic findings, or psychiatric disorder.
20. Other malignancies within 5 years (except adequately treated cervical carcinoma in situ or basal-cell skin cancer).
21. Clinically relevant thyroid dysfunction (TT4, TT3, FT3, FT4, TSH outside normal limits per investigator).
22. Active autoimmune disease (e.g. psoriasis, RA) or any condition requiring chronic immunosuppressive therapy.
23. Known or suspected CNS metastases.
24. Single target lesion \> 4 cm in longest diameter (or \> 4 cm short axis for lymph nodes) before leukapheresis.
25. Symptomatic ascites or ascites requiring repeated paracentesis or intraperitoneal therapy; small-volume radiologic ascites permitted if asymptomatic.
26. Any other condition that, in the opinion of the investigator, renders the subject unsuitable for participation.

主要终点：Incidence and Grading of Adverse Events (AEs) and Serious Adverse Events (SAEs)（Including CRS and ICANS） · This outcome measure assesses the incidence and severity grading of all Adverse Events (AEs) and Serious Adverse Events (SAEs) in subjects. Specifically: a) Cytokine Release Syndrome (CRS) and Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) are graded according to the ASTCT (American Society for Transplantation and Cellular Therapy) consensus criteria; b) All other AEs are graded according to the NCI-CTCAE (National Cancer Institute Common Terminology Criteria for Adverse Events) Version 5.0. Data are collected from leukapheresis enrollment to the end of the follow-up period. · From leukapheresis enrollment up to 15 years post-CBG131 infusion, or until study withdrawal, loss to follow-up, or death of the subject, whichever comes first.；Incidence and Determination of Dose-Limiting Toxicity (DLT) Related to CBG131 · Dose-Limiting Toxicity (DLT) refers to CBG131-related toxicities (excluding infections and malignancies) occurring within 28 days after CAR-T cell infusion. DLT is determined based on the following criteria: 1) Grade 5 AE; 2) Grade 4 CRS; 3) Grade 4 neurotoxicity; 4) Grade 3 CRS or neurotoxicity that persists for more than 72 hours and fails to improve to ≤Grade 2; 5) Other Grade 4 non-hematologic toxicity that persists for more than 72 hours and fails to improve to ≤Grade 3; 6) Other Grade 3 non-hematologic toxicity that persists for ≥2 weeks; 7) Grade 4 hematologic toxicity that persists for more than 72 hours and fails to improve to ≤Grade 3; 8) Hematologic toxicity of Grade \>3 that persists for more than 2 weeks and fails to improve to ≤Grade 2. · Within 28 days after CAR-T cell infusion.；Maximum Tolerated Dose (MTD) and Optimal Dosage of CBG131（Determined by 3+3 Dose-Escalation Schema） · This Phase I trial adopts a conventional 3 + 3 dose-escalation schema to determine the Maximum Tolerated Dose (MTD) of CBG131 and further confirm its optimal dosage. The dose cohorts are designed as follows: (1) DL1 (de-escalation cohort): 0.5×10⁸ CAR⁺ T cells; (2) DL1 (starting dose cohort): 1×10⁸ CAR⁺ T cells; (3) DL2: 2×10⁸ CAR⁺ T cells. Three subjects are enrolled in each cohort. If no DLT occurs in a cohort, dose escalation proceeds to the next higher cohort; if one DLT occurs, the cohort is expanded by an additional three subjects at the same dose. During the expansion phase: (1) If one or more additional DLTs occur in the DL1 (starting dose cohort), dose escalation is suspended and de-escalation is considered; (2) If one or more additional DLTs occur in DL2 or higher cohorts, dose escalation stops, and the previous dose is declared as the MTD. If no additional DLTs occur during expansion, dose escalation continues. · Within 28 days after CAR-T cell infusion (DLT assessment period); the MTD is determined after completion of dose escalation for all cohorts.
次要终点：Tumor CLDN18.2 Expression Positivity (Assessed by Immunohistochemistry [IHC])；Progression-Free Survival (PFS) per RECIST 1.1 Criteria；Overall Survival (OS)；Best Overall Response Rate (BORR) per RECIST 1.1 Criteria（Proportion of Subjects Achieving Complete Response [CR] or Partial Response [PR]）；CAR-T Cell Persistence in Vivo (Assessed by Peripheral Blood qPCR for CAR Transgene Copies [copies/μg gDNA])；Serum Interleukin-2 (IL-2) Concentration (Assessed by Lab Cytokine Assay)；3-month Objective Response Rate (ORR) per RECIST 1.1 Criteria（Proportion of Subjects Achieving CR or PR）；Duration of Response (DOR) per RECIST 1.1 Criteria

• CBG131 CAR-T Cell Injection · EXPERIMENTAL · This Phase I trial follows a conventional 3 + 3 dose-escalation schema. The dose cohorts are designed as follows: (1) DL1 (de-escalation cohort): 0.5×10⁸ CAR⁺ T cells; (2) DL1 (starting dose cohort): 1×10⁸ CAR⁺ T cells; (3) DL2: 2×10⁸ CAR⁺ T cells. Three subjects are enrolled in each cohort.The dose escalation rule is as follows: Absence of Dose-Limiting Toxicity (DLT) permits escalation to the next higher cohort; one DLT triggers expansion of the current cohort by three additional subjects at the same dose. If one or more additional DLTs occur during the expansion phase: (1) For the DL1 (starting dose cohort), dose escalation is suspended and de-escalation is considered; (2) For DL2 or higher cohorts, dose escalation stops, and the preceding dose is declared as the Maximum Tolerated Dose (MTD). If no further DLTs occur during expansion, dose escalation proceeds.

The goal of this clinical trial is to learn if CBG131 works to treat advanced gastric cancer or pancreatic cancer in adults whose tumors are CLDN18.2-positive. It will also learn about the safety of CBG131 and find the best dose to use. The main questions it aims to answer are: Is CBG131 safe, and what medical problems do participants have when receiving it? Does CBG131 shrink tumors in participants with CLDN18.2-positive cancers? How long do the CAR-T cells stay and work in the body? Researchers will test different doses of CBG131 to see which dose is safest and most effective. This is an early-stage trial, so there is no placebo group-everyone who joins will receive the actual treatment. Participants will: Have their blood cells collected through a procedure called leukapheresis (so the CAR-T cells can be made). Receive chemotherapy for 3 days to prepare their body for the CAR-T cells Get a single infusion of CBG131 CAR-T cells through an IV. Visit the clinic frequently for the first month, then regularly for 2 years for checkups, blood tests, and tumor assessments. Keep track of their symptoms and any side effects they experience.