# Phage-based therapeutic gene delivery targeting multiple compartments in solid tumors > **NIH NIH R21** · RUTGERS BIOMEDICAL AND HEALTH SCIENCES · 2024 · $403,686 ## Abstract ABSTRACT Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer that accounts for approximately 10-20% of all breast carcinomas and is often associated with poor prognosis. While conventional therapies such as chemotherapy, radiotherapy, and immunotherapies help the management of TNBC, most patients still develop distant metastasis and have a low overall survival rate. To date, there are only a few specific treatment options approved for this tumor subgroup, and the development of novel targeted therapies is an unmet need. Importantly, TNBC often presents as advanced disease, and these tumors are also often bereft of recognized molecular targets that can be found in other subtypes, limiting their therapeutic options. However, tumor- associated macrophage (TAM) infiltration in TNBC is frequently observed, and the complex interplay between immune cells and tumor cells within the tumor microenvironment (TME) can lead to disease progression. Specifically, signals generated in the TME can cause immunosuppression, promoting angiogenesis and immune evasion, which leads to tumor development. The interplay of M1 and M2 macrophage populations that coincide with these tumor markers are particularly important in the TME. Moreover, a high density of TAMs, particularly M2 macrophages, is associated with poorer outcomes in various cancers, including TNBC. This provides a strong basis for exploiting TAMs as potential therapeutic targets. Specifically, novel efforts to increase M2 to M1 repolarization are promising therapeutic approaches in TNBC. Here we propose a two-pronged approach to target the M2-rich TAM population, reversing immune subversion, combined with the targeted destruction of the tumor cell population, using a gene delivery approach. Prokaryotic viruses such as bacteriophage have no tropism for mammalian cells, but can be engineered to deliver genes with low efficiency. On the other hand, animal viruses have potential for targeted gene therapy but require elimination of native tropism for mammalian cells, so we combined the favorable biological attributes of eukaryotic and prokaryotic viruses to facilitate targeted systemic gene therapy applications. In Aim 1, we will explore the unique attributes of AAVP, a targeted hybrid vector containing cis-genomic elements from adeno-associated virus (AAV) and phage (P) displaying ligand motifs to target multiple compartments of TNBC—tumor cell and associated vasculature with RGD4C and TAM with CSSTRESAC—and deliver human tumor necrosis factor (TNF) to modulate the tumor microenvironment in a syngeneic model of TNBC. Aim 2 is dedicated to the characterization of the immunomodulatory effects of TNF expression within the tumor microenvironment and the potential repolarization of anti-inflammatory M2-like TAMs to a pro-inflammatory M1-like TAM population. ## Key facts - **NIH application ID:** 10986635 - **Project number:** 1R21CA283355-01A1 - **Recipient organization:** RUTGERS BIOMEDICAL AND HEALTH SCIENCES - **Principal Investigator:** WADIH ARAP - **Activity code:** R21 (R01, R21, SBIR, etc.) - **Funding institute:** NIH - **Fiscal year:** 2024 - **Award amount:** $403,686 - **Award type:** 1 - **Project period:** 2024-06-01 → 2026-05-31 ## Primary source NIH RePORTER: https://reporter.nih.gov/project-details/10986635 ## Citation > US National Institutes of Health, RePORTER application 10986635, Phage-based therapeutic gene delivery targeting multiple compartments in solid tumors (1R21CA283355-01A1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10986635. Licensed CC0. --- *[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*