(M1130-10-54) Advancing Treatment for Metastatic Triple Negative Breast Cancer: Liposomal Oncolytic Adenovirus as a Novel Neoadjuvant Therapy

Purpose: Adenovirus type-5 (Ad) is considered a prominent viral vector in cancer therapy due to its modifiability for the selective lysis of cancer cells. However, challenges are posed in Ad delivery to cancers lacking coxsackievirus and adenovirus receptors (CARs). In response to this limitation, Ad-encapsulated DOTAP-folate liposomes were developed, which improved Ad delivery and heightened therapeutic efficacy through membrane fusion and folate receptor-mediated endocytosis.

Methods: The 4T1-eGFP mammary carcinoma model, a CAR-negative triple-negative breast cancer (TNBC) cell line (ER-, PR-, HER2-), resistant to adenoviral infection, was utilized to study the comparative in vivo transduction of oncolytic Ad-hTERT driven by a human telomerase promoter. The study assessed Ad-hTERT with and without DOTAP-folate liposomal encapsulation, manufactured via extrusion or homogenization techniques, with spontaneous encapsulation through charge interaction. CAR-negative TNBC 4T1-eGFP tumor-bearing immunocompetent BALB/c mice were treated via intratumoral injections with Ad-hTERT, both with and without DOTAP-folate liposomal encapsulation, to evaluate the efficacy of the encapsulated versus unencapsulated oncolytic adenovirus.

Results: CAR-negative 4T1-eGFP tumors in immunocompetent BALB/c mice implanted in the mammary fat pad exhibited superior oncolytic activity of Ad-hTERT when encapsulated in DOTAP-folate liposomes compared to the unencapsulated form. This was assessed by measurements of tumor volume (p < 0.01), tumor size appearance, and tumor weights (p < 0.001).

Conclusion: DOTAP-folate liposomal encapsulation enhances the efficacy of oncolytic Ad-hTERT in CAR-negative TNBC cells, establishing it as an optimal therapy for tumors with CAR heterogeneity. Ongoing in vivo studies with immunocompetent BALB/c mice will investigate post-surgical metastasis, survival probability, and immunohistochemical pathological analysis to study various markers, including CD3, NK1.1, F4/80, CASPASE-3, and Ki-67.

References: 1. Huang, Ching-Hsin, Tao Dong, Abraham T. Phung, Jaimin R. Shah, Christopher Larson, Ana B. Sanchez, Sarah L. Blair et al. "Full remission of CAR-deficient tumors by DOTAP-folate liposome encapsulation of adenovirus." ACS Biomaterials Science & Engineering 8, no. 12 (2022): 5199-5209.
2.Shah, Jaimin R., Tao Dong, Abraham T. Phung, Tony Reid, Christopher Larson, Ana B. Sanchez, Bryan Oronsky et al. "Development of Adenovirus Containing Liposomes Produced by Extrusion vs. Homogenization: A Comparison for Scale-Up Purposes." Bioengineering 9, no. 11 (2022): 620.
3. Dong, Tao, Jaimin R. Shah, Abraham T. Phung, Christopher Larson, Ana B. Sanchez, Omonigho Aisagbonhi, Sarah L. Blair et al. "A local and abscopal effect observed with liposomal encapsulation of intratumorally injected oncolytic adenoviral therapy." Cancers 15, no. 12 (2023): 3157.

Acknowledgements: The authors declare that they have no conflict of interest.