PMID- 30154145 OWN - NLM STAT- MEDLINE DCOM- 20191007 LR - 20191007 IS - 1538-7445 (Electronic) IS - 0008-5472 (Linking) VI - 78 IP - 21 DP - 2018 Nov 1 TI - Intrathecal Viral Vector Delivery of Trastuzumab Prevents or Inhibits Tumor Growth of Human HER2-Positive Xenografts in Mice. PG - 6171-6182 LID - 10.1158/0008-5472.CAN-18-0363 [doi] AB - 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. (c)2018 AACR. CI - (c)2018 American Association for Cancer Research. FAU - Rothwell, William T AU - Rothwell WT AUID- ORCID: 0000-0001-5251-4714 AD - Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Bell, Peter AU - Bell P AD - Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Richman, Laura K AU - Richman LK AD - Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Limberis, Maria P AU - Limberis MP AD - Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Tretiakova, Anna P AU - Tretiakova AP AD - Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Li, Mingyao AU - Li M AD - Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. AD - Department of Biostatistics and Epidemiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. FAU - Wilson, James M AU - Wilson JM AD - Gene Therapy Program, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania. wilsonjm@upenn.edu. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20180828 PL - United States TA - Cancer Res JT - Cancer research JID - 2984705R RN - 0 (Homeodomain Proteins) RN - 128559-51-3 (RAG-1 protein) RN - EC 2.7.10.1 (ERBB2 protein, human) RN - EC 2.7.10.1 (Receptor, ErbB-2) RN - P188ANX8CK (Trastuzumab) SB - IM MH - Animals MH - Brain Neoplasms/secondary/*therapy MH - Breast Neoplasms/pathology/*therapy MH - Dependovirus/metabolism MH - Drug Delivery Systems MH - Female MH - Genetic Vectors MH - Homeodomain Proteins/genetics MH - Humans MH - Injections, Spinal/*methods MH - Macaca MH - Macrophages/metabolism MH - Mice MH - Mice, Inbred NOD MH - Neoplasm Metastasis MH - Neoplasms/*metabolism MH - Receptor, ErbB-2/*metabolism MH - Trastuzumab/*administration & dosage MH - Xenograft Model Antitumor Assays EDAT- 2018/08/30 06:00 MHDA- 2019/10/08 06:00 CRDT- 2018/08/30 06:00 PHST- 2018/02/02 00:00 [received] PHST- 2018/07/09 00:00 [revised] PHST- 2018/08/23 00:00 [accepted] PHST- 2018/08/30 06:00 [pubmed] PHST- 2019/10/08 06:00 [medline] PHST- 2018/08/30 06:00 [entrez] AID - 0008-5472.CAN-18-0363 [pii] AID - 10.1158/0008-5472.CAN-18-0363 [doi] PST - ppublish SO - Cancer Res. 2018 Nov 1;78(21):6171-6182. doi: 10.1158/0008-5472.CAN-18-0363. Epub 2018 Aug 28.