Intratumoral Macrophage Exosomes With Mechanobiological Reprogramming for Advanced Solid Tumors

A Phase I, Open-Label, Dose-Escalation Clinical Study to Evaluate the Safety and Tolerability of Intratumoral Administration of Macrophage-Derived Exosomes With Cellular Mechanobiological Reprogramming in Patients With Advanced Solid Tumors

The goal of this phase I clinical trial is to evaluate the safety and tolerability of intratumoral injection of mechanically reprogrammed macrophage-derived exosomes (MRMEs) in adults aged 18-65 years with advanced solid tumors who have failed, are ineligible for, or are intolerant of standard therapies.

Inclusion Criteria:

1. Age 18 to 65 years (inclusive) at screening, any gender.

2. Histologically or cytologically confirmed advanced (unresectable or metastatic) solid tumors (including melanoma, soft tissue sarcoma, head and neck squamous cell carcinoma, etc.) that have failed standard therapy, have no standard treatment options, or are intolerant to standard treatment.

3. Must have a primary lesion suitable for local injection, accessible by direct palpation or under ultrasound/CT image guidance.

4. At least one measurable lesion per RECIST v1.1 criteria.

5. ECOG performance status score of 0-2.

6. Expected survival ≥ 3 months.

7. Adequate organ function within 7 days prior to treatment:

   • Neutrophil count (NEUT#) ≥ 1.5×10^9/L; Platelets (PLT) ≥ 80×10^9/L; Hemoglobin ≥ 8 g/dL
   • AST, ALT, ALP ≤ 2.5×ULN; Total bilirubin (TBIL) ≤ 1.5×ULN; Albumin ≥ 2.8 g/dL
   • Serum creatinine ≤ 1.5×ULN or CCR > 60 ml/min
   • INR ≤ 1.5; APTT ≤ 1.5×ULN

8. Voluntarily participates, signs informed consent, and is able to comply with study visits and procedures.

Exclusion Criteria:

1. Contraindications to intratumoral injection: inflammation or ulceration at injection site; severe bleeding tendency; abnormal or permanent body art (e.g., tattoos) at injection site interfering with local reaction observation.
2. History of other malignancies (except cured basal cell carcinoma, squamous cell carcinoma of skin, superficial bladder cancer, cervical carcinoma in situ, intramucosal gastrointestinal cancer without recurrence for 5 years).
3. Active autoimmune disease or history of autoimmune disease (including but not limited to immune-related neuropathy, multiple sclerosis, autoimmune neuropathy, Guillain-Barré syndrome, myasthenia gravis, SLE, connective tissue disease, scleroderma, IBD, autoimmune hepatitis, TEN, or Stevens-Johnson syndrome); except Type 1 diabetes on stable insulin dose.
4. Anti-tumor vaccine within 4 weeks before first dose; live vaccines within 4 weeks before or during the study; major surgery or severe trauma within 4 weeks before first dose.
5. Prior anti-tumor treatment toxicity not recovered to ≤ CTCAE v5.0 Grade 1.
6. Serious medical conditions: NYHA Class II or higher heart dysfunction, ischemic heart disease, significant arrhythmia, poorly controlled diabetes (fasting glucose ≥ 10 mmol/L), uncontrolled hypertension (SBP > 150 mmHg and/or DBP > 100 mmHg), LVEF < 50%, QTc > 450 ms (male) or > 470 ms (female).
7. Active tuberculosis or uncontrolled prior TB infection.
8. Hyperthyroidism or organic thyroid disease (except hypothyroidism controlled with stable thyroid hormone replacement).
9. Active infection or unexplained fever within 48 hours before first dose, or systemic antibiotics within 1 week before informed consent.
10. Active HBV (HBV DNA ≥ 2000 IU/ml or 10^4 copies/ml), active HCV (HCV antibody positive and HCV RNA above detection limit), or known HIV positive or AIDS history.
11. Known neurological or psychiatric disorders (e.g., epilepsy, dementia).
12. Known history of drug abuse or alcohol abuse within 3 months.
13. Pregnant or breastfeeding women; participants (or their partners) planning pregnancy or unwilling to use contraception from screening to 6 months after study completion.
14. Receipt of any investigational drug within 4 weeks before first dose, or concurrent enrollment in another interventional clinical study.
15. Any other factors judged by the investigator that may affect study completion.