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Published on: April 16, 2019
Phase I clinical trial of systemically administered TUSC2(FUS1)-nanoparticles mediating functional gene transfer in
Charles Lu1, David J Stewart, J Jack Lee
1The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America. clu@mdanderson.org
Background:
Tumor suppressor gene TUSC2/FUS1 (TUSC2) is frequently inactivated early in lung cancer development. TUSC2 mediates apoptosis in cancer cells but not normal cells by upregulation of the intrinsic apoptotic pathway. No drug strategies currently exist targeting loss-of-function genetic abnormalities. We report the first in-human systemic gene therapy clinical trial of tumor suppressor gene TUSC2.
Methods:
Patients with recurrent and/or metastatic lung cancer previously treated with platinum-based chemotherapy were treated with escalating doses of intravenous N-[1-(2,3-dioleoyloxy)propyl]-N,N,N-trimethylammonium chloride (DOTAP):cholesterol nanoparticles encapsulating a TUSC2 expression plasmid (DOTAP:chol-TUSC2) every 3 weeks.
Results:
Thirty-one patients were treated at 6 dose levels (range 0.01 to 0.09 milligrams per kilogram). The MTD was determined to be 0.06 mg/kg. Five patients achieved stable disease (2.6-10.8 months, including 2 minor responses). One patient had a metabolic response on positron emission tomography (PET) imaging. RT-PCR analysis detected TUSC2 plasmid expression in 7 of 8 post-treatment tumor specimens but not in pretreatment specimens and peripheral blood lymphocyte controls. Proximity ligation assay, performed on paired biopsies from 3 patients, demonstrated low background TUSC2 protein staining in pretreatment tissues compared with intense (10-25 fold increase) TUSC2 protein staining in post-treatment tissues. RT-PCR gene expression profiling analysis of apoptotic pathway genes in two patients with high post-treatment levels of TUSC2 mRNA and protein showed significant post-treatment changes in the intrinsic apoptotic pathway. Twenty-nine genes of the 82 tested in the apoptosis array were identified by Igenuity Pathway Analysis to be significantly altered post-treatment in both patients (Pearson correlation coefficient 0.519; p<0.01).
Conclusions:
DOTAP:chol-TUSC2 can be safely administered intravenously in lung cancer patients and results in uptake of the gene by human primary and metastatic tumors, transgene and gene product expression, specific alterations in TUSC2-regulated pathways, and anti-tumor effects (to our knowledge for the first time for systemic DOTAP:cholesterol nanoparticle gene therapy).
Trial Registration:
ClinicalTrials.gov NCT00059605.
Insights
This study reports the first human gene therapy trial for lung cancer using TUSC2 (tumor suppressor gene) delivered via DOTAP:cholesterol nanoparticles. The treatment showed safety, tumor uptake, gene expression, and anti-tumor effects, offering a new strategy for lung cancer.
Area of Science:
- Oncology
- Gene Therapy
- Nanomedicine
Background:
- Tumor suppressor gene TUSC2 is frequently inactivated in lung cancer.
- TUSC2 induces apoptosis in cancer cells via the intrinsic apoptotic pathway.
- No current treatments target loss-of-function genetic abnormalities in lung cancer.
Purpose of the Study:
- To evaluate the safety and efficacy of systemic gene therapy using TUSC2 in lung cancer patients.
- To assess tumor gene uptake, expression, and downstream pathway modulation.
- To establish the maximum tolerated dose (MTD) for DOTAP:chol-TUSC2 therapy.
Main Methods:
- First-in-human, dose-escalation clinical trial (NCT00059605) of intravenous DOTAP:chol-TUSC2 in recurrent/metastatic lung cancer patients.
- Patients received escalating doses every 3 weeks.
- Tumor biopsies and PET imaging were used to assess gene delivery, expression, and response.
Main Results:
- The MTD was determined to be 0.06 mg/kg.
- TUSC2 plasmid and protein expression were detected in post-treatment tumors.
- Five patients achieved stable disease, and one showed a metabolic response.
- Significant alterations in the intrinsic apoptotic pathway were observed in patients with high TUSC2 expression.
Conclusions:
- Systemic DOTAP:chol-TUSC2 gene therapy is safe in lung cancer patients.
- The therapy leads to gene and protein expression in tumors.
- DOTAP:chol-TUSC2 demonstrates anti-tumor effects and modulates TUSC2-regulated pathways.
- This represents a novel approach for systemic nanoparticle gene therapy.
