CELL INTELLIGENCE · 肿瘤细胞治疗研究

Inclusion Criteria:

* Aged 18 to 75 years (inclusive) at the time of signing the informed consent form, with no gender restriction.
* Histologically or cytologically confirmed advanced solid tumor (partial laboratory test results are acceptable):

HER2-positive: IHC 3+ or IHC 2+ with ISH+ PSMA+++: Intensity score 2+ with proportion ≥ 30%, or intensity score 3+ with proportion ≥ 10% FAP+++: Intensity score 2+ with proportion ≥ 30%, or intensity score 3+ with proportion ≥ 10%

Disease status:

Subjects (HER2-targeted): Patients with advanced solid tumor who are refractory to or intolerant of DS-8201 treatment.

Subjects (PSMA-targeted): Patients with advanced solid tumor who are refractory to or intolerant of first- or second-line treatment.

Subjects (FAP-targeted): Patients with advanced solid tumor who are refractory to or intolerant of first- or second-line treatment.

* Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
* Life expectancy of at least 3 months (as assessed by the investigator).
* Adequate organ function, defined as follows:

Hematologic: Hemoglobin ≥ 90 g/L, absolute neutrophil count (ANC) ≥ 1.5 × 10⁹/L, platelet count ≥ 80 × 10⁹/L Hepatic: Total bilirubin ≤ 1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) / alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN in patients with liver metastases) Renal: Serum creatinine ≤ 1 × ULN, or creatinine clearance (CrCl) ≥ 50 mL/min (calculated by the Cockcroft-Gault formula) Cardiac: Left ventricular ejection fraction (LVEF) ≥ 50% (assessed by ECHO or MUGA) Pancreatic: Serum amylase / lipase ≤ 1.5 × ULN

* Electrolytes: Corrected calcium, potassium, and magnesium levels within the normal range.
* Subjects must have at least one measurable lesion as defined by RECIST Version 1.1.
* Adequate venous access for apheresis with no contraindications.
* Tolerability to G-CSF: No history of severe hypersensitivity to filgrastim or its biosimilars.
* Subjects must fully understand the purpose, nature, methods, and potential adverse reactions of the study, and voluntarily participate in the study and sign the informed consent form prior to initiation of any study procedures.

Exclusion Criteria:

* Known hypersensitivity to CAR-M or any of its excipients.
* History of severe hypersensitivity to filgrastim (G-CSF) or tocilizumab.
* Known history of substance abuse.
* A history of ≥ Grade 3 immune-related adverse events (irAEs) or ≥ Grade 2 immune-related myocarditis following prior immunotherapy.
* Active infection requiring systemic therapy, except for the following conditions: uncomplicated urinary tract infection (UTI) (afebrile and resolved after 3 days of antibiotic therapy) or bacterial pharyngitis (confirmed by GAS testing and treated with appropriate antibiotics).
* HIV infection, active hepatitis B virus (HBV) infection (HBV DNA \> upper limit of normal \[ULN\]), or active hepatitis C virus (HCV) infection (HCV RNA \> ULN).
* History of malignant neoplasm other than the following within the past 5 years:

Curable malignant neoplasms (e.g., basal cell carcinoma, carcinoma in situ of the cervix/breast, or cutaneous squamous cell carcinoma).

* Malignant neoplasms with a favorable prognosis (e.g., papillary thyroid carcinoma, carcinoma in situ of the skin or breast), regardless of whether they have been cured or not.
* Receipt of other investigational drugs or therapies within 4 weeks prior to the first administration of CAR-M, or ongoing participation in the safety follow-up period of other investigational drugs or therapies.
* Presence of severe, non-healing wounds, ulcers, or fractures within 4 weeks prior to the first administration of CAR-M.
* History of substance abuse or psychiatric disorders.
* History of severe cardiovascular and cerebrovascular diseases, including but not limited to:
* Acute events: myocardial infarction, stroke, or New York Heart Association (NYHA) Class III-IV heart failure within 6 months.
* Thromboembolism: symptomatic deep vein thrombosis or pulmonary embolism (DVT/PE) within 6 months (unless on stable anticoagulant therapy).
* Arrhythmia: ventricular arrhythmia requiring intervention or Grade II-III atrioventricular block.
* Confirmed pulmonary fibrosis, interstitial pneumonitis, pneumoconiosis, radiation pneumonitis, or severe pulmonary dysfunction.
* For patients with prior treatment: ≥ Grade 2 hematological toxicity or ≥ Grade 3 non-hematological toxicity per the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) v5.0, except for toxicities deemed to pose no safety risk by the investigator (e.g., alopecia, Grade 2 peripheral neuropathy).
* Indwelling catheters/drainage tubes (excluding central venous catheters).
* Central nervous system (CNS) disorders: epilepsy, stroke, dementia, or autoimmune diseases involving the CNS.
* Active or untreated brain or CNS disorders, including brain metastases that have not stabilized for ≥ 8 weeks after radiotherapy, symptomatic brain metastases, or cytologically confirmed carcinomatous meningitis.

Severe immunodeficiency.

* History of prior transplantation: allogeneic stem cell transplantation or solid organ transplantation.
* Active autoimmune disease requiring systemic immunosuppression (prednisone dose \> 10 mg/day or equivalent).
* History of high-risk autoimmune diseases with potential for recurrence (e.g., systemic lupus erythematosus \[SLE\], rheumatoid arthritis \[RA\], inflammatory bowel disease \[IBD\]). Exceptions: stable vitiligo/psoriasis, hormone-replaced hypothyroidism, or well-controlled Type 1 diabetes mellitus (HbA1c ≤ 7%).
* Use of systemic glucocorticoids (prednisone \> 10 mg/day) or other immunosuppressants within 14 days (exceptions: topical/inhaled steroids, adrenal replacement therapy).
* Receipt of major organ surgery, severe trauma, or invasive dental procedures (e.g., tooth extraction, dental implantation) within 4 weeks prior to the first administration of CAR-M, or planned elective surgery during the study period.
* Active autoimmune disease or history of recurrent autoimmune disease (excluding well-controlled Type 1 diabetes mellitus; hypothyroidism manageable with hormone replacement therapy alone; or dermatological conditions not requiring systemic therapy, e.g., vitiligo or psoriasis).
* Presence of active infection requiring systemic anti-infective therapy.
* Positive pregnancy test in women of childbearing potential (WOCBP).
* Refusal to use effective contraceptive measures from the time of informed consent until 1 year after treatment.

主要终点：Incidence of Dose-Limiting Toxicities (DLTs) · Incidence and characteristics of DLTs graded according to NCI CTCAE v5.0. The DLT observation period is 28 days post-infusion. · Within 28 days after the first infusion；Incidence of Adverse Events (AEs) · Incidence and severity of treatment-emergent adverse events (TEAEs) graded according to NCI CTCAE v5.0. · From signing ICF until 24 months after the last infusion.；Determine and characterize the optimal dosing regimen (full dose vs. split dose). · Split dose is superior for CAR-M optimal dosing: it mitigates acute toxicities (e.g., cytokine responses) via gradual immune activation, sustains robust CAR-M cell expansion and in vivo persistence, and improves safety in high-risk patients. Full dose enables rapid therapeutic efficacy in low-risk cohorts with intact organ function. Optimal regimens are tailored to patient baseline status/indications, validated via dose-escalation trials for balance of safety and anti-tumor activity. · Day 0, Day 7, Day 14
次要终点：To obtain the pharmacokinetic (PK) characteristics of CAR-M (targeting HER2, PSMA, FAP, etc.) injection in humans.；Serum Cytokines of CAR-M (targeting HER2, PSMA, FAP, etc.) injection in humans.；Tumor Microenvironment (TME) Infiltration；Dynamic Monitoring of Target Expression；ORR (Objective Response Rate)；DOR (Duration of Response)；DCR (Disease Control Rate)；PFS (Progression-Free Survival)

• Cohort 1: Split-dose administration · EXPERIMENTAL · Total dose: 5.0×10⁹ cells Day 1: 50% of the total dose Day 7: The remaining 50% of the dose \[only if no ≥Grade 2 chronic kidney syndrome/nephrotoxicity is observed after the first dose\]
• Cohort 2: Bolus administration · EXPERIMENTAL · Total dose: 5.0×10⁹ cells Day 1: Full dose

This is a single-arm, open-label, single-center, dose-escalation platform clinical trial design. Using an adenovirus vector platform, the study aims to evaluate the safety, tolerability, pharmacokinetic characteristics, and preliminary anti-tumor activity of investigational CAR-M macrophage injections targeting various antigens (including HER2, PSMA, FAP, etc.) in patients with advanced solid tumors. The clinical trial is designed to be conducted in cohorts, with patients enrolled into respective cohorts based on target antigen and indication screening