Intrathecal Viral Vector Delivery of Trastuzumab Prevents or Inhibits Tumor Growth of Human HER2-Positive Xenografts in Mice.

Abstract

Breast cancer brain metastases are a deadly sequela of primary breast tumors that overexpress human epidermal growth factor receptor 2 (HER2); median survival for patients with these tumors is 10 to 13 months from the time of diagnosis. Current treatments for HER2-positive breast cancer brain metastases are invasive, toxic, and largely ineffective. Here, we have developed an adeno-associated virus serotype 9 (AAV9) vector to express the anti-HER2 monoclonal antibody trastuzumab (Herceptin) in vivo A single prophylactic intrathecal administration of AAV9.trastuzumab vector in a novel orthotopic Rag1-/- murine xenograft model of HER2-positive breast cancer brain metastases significantly increased median survival, attenuated brain tumor growth, and preserved both the HER2 antigen specificity and the natural killer cell-associated mechanism of action of trastuzumab. When administered as a tumor treatment, AAV9.trastuzumab increased median survival. Dose-escalation studies revealed that higher doses of AAV9.trastuzumab resulted in smaller tumor volumes. Our results indicate that intrathecal AAV9.trastuzumab may provide significant antitumor activity in patients with HER2-positive breast cancer brain metastases.Significance: Intrathecal delivery of trastuzumab via adeno-associated virus has the potential to become a novel, integral part of adjuvant therapy for patients with HER2-positive breast cancer brain metastases. Cancer Res; 78(21); 6171-82. ©2018 AACR.

• Authors: William T Rothwell, Peter Bell, Laura K Richman, Maria P Limberis, Anna P Tretiakova, Mingyao Li, James M Wilson
• Journal: Cancer research (Cancer Res) Vol. 78 Issue 21 Pg. 6171-6182 (11 01 2018) ISSN: 1538-7445 [Electronic] United States
• PMID: 30154145 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Homeodomain Proteins
• RAG-1 protein
• ERBB2 protein, human
• Receptor, ErbB-2
• Trastuzumab

Topics

• Animals
• Brain Neoplasms (secondary, therapy)
• Breast Neoplasms (pathology, therapy)
• Dependovirus (metabolism)
• Drug Delivery Systems
• Female
• Genetic Vectors
• Homeodomain Proteins (genetics)
• Humans
• Injections, Spinal (methods)
• Macaca
• Macrophages (metabolism)
• Mice
• Mice, Inbred NOD
• Neoplasm Metastasis
• Neoplasms (metabolism)
• Receptor, ErbB-2 (metabolism)
• Trastuzumab (administration & dosage)
• Xenograft Model Antitumor Assays