Intratumoral Macrophage Exosomes With Mechanobiological Reprogramming for Advanced Solid Tumors

Official title

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

Overview

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.

Interventions

• Biological Mechanobiologically Reprogrammed Macrophage-Derived Exosomes (1×10^10 exosomes)
  Autologous macrophage-derived exosomes prepared from the participant's own peripheral blood monocytes. Monocytes are isolated by apheresis, differentiated into macrophages, subjected to nuclear compression via a microfluidic device to induce mechanobiological reprogramming, and then exosomes are extracted and purified by ultracentrifugation. Administered via intratumoral injection once every 2 weeks for 4 doses at a dose of 1×10\^10 exosomes.
• Biological Mechanobiologically Reprogrammed Macrophage-Derived Exosomes (2.5×10^10 exosomes)
  Autologous macrophage-derived exosomes prepared from the participant's own peripheral blood monocytes. Monocytes are isolated by apheresis, differentiated into macrophages, subjected to nuclear compression via a microfluidic device to induce mechanobiological reprogramming, and then exosomes are extracted and purified by ultracentrifugation. Administered via intratumoral injection once every 2 weeks for 4 doses at a dose of 2.5×10\^10 exosomes.
• Biological Mechanobiologically Reprogrammed Macrophage-Derived Exosomes (5×10^10 exosomes)
  Autologous macrophage-derived exosomes prepared from the participant's own peripheral blood monocytes. Monocytes are isolated by apheresis, differentiated into macrophages, subjected to nuclear compression via a microfluidic device to induce mechanobiological reprogramming, and then exosomes are extracted and purified by ultracentrifugation. Administered via intratumoral injection once every 2 weeks for 4 doses at a dose of 5×10\^10 exosomes.

Primary outcome measures

• Incidence of Dose-Limiting Toxicity (DLT) [Time frame: From first administration through Day 28 post-administration (approximately 4 weeks)]

Secondary outcome measures (4)

• Objective Response Rate (ORR) [Time frame: Up to 12 months]
• Progression-Free Survival (PFS) [Time frame: Up to 24 months]
• Overall Survival (OS) [Time frame: Up to 24 months]
• Incidence of Treatment-Emergent Adverse Events (TEAEs) [Time frame: Up to 6 months]

Eligibility criteria

Inclusion criteria

• Age 18 to 65 years (inclusive) at screening, any gender.
• 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.
• Must have a primary lesion suitable for local injection, accessible by direct palpation or under ultrasound/CT image guidance.
• At least one measurable lesion per RECIST v1.1 criteria.
• ECOG performance status score of 0-2.
• Expected survival ≥ 3 months.
• 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
• Voluntarily participates, signs informed consent, and is able to comply with study visits and procedures.

Exclusion criteria

• 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.
• 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).
• 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.
• 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.
• Prior anti-tumor treatment toxicity not recovered to ≤ CTCAE v5.0 Grade 1.
• 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).
• Active tuberculosis or uncontrolled prior TB infection.
• Hyperthyroidism or organic thyroid disease (except hypothyroidism controlled with stable thyroid hormone replacement).
• Active infection or unexplained fever within 48 hours before first dose, or systemic antibiotics within 1 week before informed consent.
• 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.
• Known neurological or psychiatric disorders (e.g., epilepsy, dementia).
• Known history of drug abuse or alcohol abuse within 3 months.
• Pregnant or breastfeeding women; participants (or their partners) planning pregnancy or unwilling to use contraception from screening to 6 months after study completion.
• Receipt of any investigational drug within 4 weeks before first dose, or concurrent enrollment in another interventional clinical study.
• Any other factors judged by the investigator that may affect study completion.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Sequential

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• West China Hospital, Sichuan University — Chengdu

Publications

• Raillard M, Love EJ, Murison PJ. Effect of predosing versus slow administration of propofol on the dose required for anaesthetic induction and on physiologic variables in healthy dogs. Vet Anaesth Analg. 2018 Jul;45(4):414-422. doi: 10.1016/j.vaa.2018.02.004. Epub 2018 Mar 6. PMID 29661678
• Alatrash N, Narh ES, Yadav A, Kim MJ, Janaratne T, Gabriel J, MacDonnell FM. Synthesis, DNA Cleavage Activity, Cytotoxicity, Acetylcholinesterase Inhibition, and Acute Murine Toxicity of Redox-Active Ruthenium(II) Polypyridyl Complexes. ChemMedChem. 2017 Jul 6;12(13):1055-1069. doi: 10.1002/cmdc.201700240. Epub 2017 Jun 12. PMID 28605571
• Okoye IS, Coomes SM, Pelly VS, Czieso S, Papayannopoulos V, Tolmachova T, Seabra MC, Wilson MS. MicroRNA-containing T-regulatory-cell-derived exosomes suppress pathogenic T helper 1 cells. Immunity. 2014 Jul 17;41(1):89-103. doi: 10.1016/j.immuni.2014.05.019. PMID 25035954
• Niu J, Liu Y. The Construction of English Smart Classroom Teaching Mode Based on Deep Learning. Comput Intell Neurosci. 2022 Aug 22;2022:9037010. doi: 10.1155/2022/9037010. eCollection 2022. PMID 36045993
• Piccolo S, Panciera T, Contessotto P, Cordenonsi M. YAP/TAZ as master regulators in cancer: modulation, function and therapeutic approaches. Nat Cancer. 2023 Jan;4(1):9-26. doi: 10.1038/s43018-022-00473-z. Epub 2022 Dec 23. PMID 36564601
• Wang H, Guo S, Kim SJ, Shao F, Ho JWK, Wong KU, Miao Z, Hao D, Zhao M, Xu J, Zeng J, Wong KH, Di L, Wong AH, Xu X, Deng CX. Cisplatin prevents breast cancer metastasis through blocking early EMT and retards cancer growth together with paclitaxel. Theranostics. 2021 Jan 1;11(5):2442-2459. doi: 10.7150/thno.46460. eCollection 2021. PMID 33500735
• Reiss KA, Angelos MG, Dees EC, Yuan Y, Ueno NT, Pohlmann PR, Johnson ML, Chao J, Shestova O, Serody JS, Schmierer M, Kremp M, Ball M, Qureshi R, Schott BH, Sonawane P, DeLong SC, Christiano M, Swaby RF, Abramson S, Locke K, Barton D, Kennedy E, Gill S, Cushing D, Klichinsky M, Condamine T, Abdou Y. CAR-macrophage therapy for HER2-overexpressing advanced solid tumors: a phase 1 trial. Nat Med. 2025 PMID 39920391
• Song Y, Soto J, Chen B, Yang L, Li S. Cell engineering: Biophysical regulation of the nucleus. Biomaterials. 2020 Mar;234:119743. doi: 10.1016/j.biomaterials.2019.119743. Epub 2020 Jan 3. PMID 31962231

Identifiers

NCT: NCT07563972 · 2026-796

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗