Liposomal oncolytic adenovirus as a neoadjuvant therapy for triple-negative breast cancer
Jaimin R Shah1,2,3, Tao Dong1,2,4, Abraham T Phung1,2,4
1Moores Cancer Center, University of California San Diego, La Jolla, CA, 92093, USA.
Abstract:
Breast cancer remains one of the leading causes of cancer-related death, with triple-negative breast cancer (TNBC) accounting for 15-20% of cases. TNBC, characterized by the absence of ER, PR, and HER2 protein, is an aggressive form of breast cancer that is unresponsive to hormonal therapies and HER2-targeted treatments, with fewer treatment options and poorer prognosis. Oncolytic adenoviruses (Ad) are a potential treatment option for TNBC but require coxsackievirus and adenovirus receptors (CAR) to effectively enter and transduce cancer cells. This study investigates a novel neoadjuvant therapy to improve the efficacy of an oncolytic Ad with human telomerase reverse transcriptase (Ad-hTERT) in CAR-low TNBC tumors using folate surface-modified liposomes to enhance delivery. This therapy helps deescalate treatment by reducing or eliminating the need for checkpoint inhibitors or toxic chemotherapy combinations. In vitro studies using CAR-low TNBC murine 4T1-eGFP cells, CAR-high TNBC human MDA-MB-231-GFP cells and several other TNBC human cancer cell lines with varying CAR expression demonstrated significantly higher cytotoxicity with encapsulated Ad-hTERT compared to Ad-hTERT. Similar results were observed in patient-derived primary TNBC cells. In vivo studies in immunocompetent mice with CAR-low 4T1-eGFP tumors revealed that encapsulated Ad-hTERT, administered as neoadjuvant therapy, resulted in stable or reduced tumor sizes, improved survival rates, higher apoptosis of cancer cells, lower cancer cell proliferation, and increased T-cell infiltration in resected tumors. Furthermore, encapsulated Ad-hTERT prevented lung metastasis and tumor recurrence at the primary site, resulting in higher survival rates in mice. Thus, liposomal encapsulation of Ad may be a viable strategy for treating TNBC.
Insights
Liposomal encapsulation of oncolytic adenoviruses enhances treatment for triple-negative breast cancer (TNBC). This novel therapy improves efficacy in CAR-low TNBC tumors, offering a promising alternative to chemotherapy.
Area of Science:
- Oncology
- Nanomedicine
- Virology
Background:
- Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options and poor prognosis.
- Oncolytic adenoviruses (Ad) show promise for TNBC but depend on coxsackievirus and adenovirus receptors (CAR) for efficacy.
- CAR-low TNBC presents a challenge for Ad-based therapies due to restricted viral entry.
Purpose of the Study:
- To investigate a novel neoadjuvant therapy using folate-modified liposomes to enhance the delivery and efficacy of an oncolytic adenovirus with human telomerase reverse transcriptase (Ad-hTERT) in CAR-low TNBC.
- To evaluate the potential of this liposomal encapsulation strategy to improve treatment outcomes and reduce reliance on chemotherapy or checkpoint inhibitors.
Main Methods:
- In vitro studies utilized CAR-low and CAR-high TNBC cell lines (murine 4T1-eGFP, human MDA-MB-231-GFP) and patient-derived TNBC cells to assess cytotoxicity of encapsulated Ad-hTERT versus free Ad-hTERT.
- In vivo studies employed immunocompetent mice bearing CAR-low 4T1-eGFP tumors, administering encapsulated Ad-hTERT as neoadjuvant therapy.
- Evaluated tumor growth, survival rates, apoptosis, proliferation, T-cell infiltration, metastasis, and recurrence.
Main Results:
- Encapsulated Ad-hTERT demonstrated significantly higher cytotoxicity in CAR-low TNBC cells compared to free Ad-hTERT.
- In vivo, neoadjuvant encapsulated Ad-hTERT led to reduced tumor size, improved survival, increased cancer cell apoptosis, decreased proliferation, and enhanced T-cell infiltration.
- The therapy effectively prevented lung metastasis and primary tumor recurrence, significantly improving overall survival.
Conclusions:
- Liposomal encapsulation of Ad-hTERT is a viable strategy to overcome CAR-low barriers in TNBC.
- This approach enhances oncolytic adenovirus efficacy, offering a potential de-escalation strategy for TNBC treatment.
- The findings support the development of liposome-encapsulated oncolytic adenoviruses as a promising therapeutic option for TNBC.
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