A Phase I Platform Study of Target-Based Screened CAR-Macrophages for the Treatment of Advanced Malignant Tumors

This study adopts a single-arm, open-label, single-center, dose-escalation platform clinical trial design, which is constructed based on an adenovirus vector delivery system. The primary objective of this trial is to systematically evaluate the safety, tolerability, pharmacokinetic profiles, and preliminary anti-tumor activity of the investigational CAR-M (chimeric antigen receptor-macrophage) injection in patients with advanced solid tumors. The investigational product targets multiple specific antigens, including but not limited to HER2 (human epidermal growth factor receptor 2), PSMA (prostate-specific membrane antigen), and FAP (fibroblast activation protein).

The trial is designed to be implemented in a cohort-based manner, with strict enrollment criteria and screening procedures to ensure the rationality and scientificity of cohort grouping. Specifically, all potential participants will first undergo comprehensive screening, which mainly includes two core aspects: target antigen detection and indication confirmation. For target antigen detection, qualified detection techniques will be used to verify the expression level of the target antigen in the patient's tumor tissue or related samples, ensuring that the patient's tumor expresses the corresponding target antigen targeted by the CAR-M injection in the cohort. For indication confirmation, the patient's clinical diagnosis, tumor stage, previous treatment history, and other relevant clinical data will be reviewed in detail to confirm that the patient meets the advanced solid tumor indication requirements corresponding to the cohort.

Only patients who pass both target antigen screening and indication screening will be enrolled into the corresponding cohort according to the matching relationship between the target antigen they express and the indication. Each cohort will focus on evaluating the investigational CAR-M injection targeting a specific antigen in patients with corresponding advanced solid tumors, and the dose-escalation process will be carried out step by step in accordance with pre-set trial protocols, so as to gradually clarify the safe dose range, pharmacokinetic characteristics, and preliminary anti-tumor effect of the product in different populations.

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.