FY25 Macrophage Derived Engineered Vesicles to Treat Pediatric Osteosarcoma

Grants and Contracts Details

Description

Osteosarcoma (OS) is a rare cancer and prior to the development of effective chemotherapy regimens, OS was nearly universally fatal. Currently, the five-year survival is approximately 66%, but metastasis remains the most important fatal complication of OS. A therapy preventing OS lung metastases would be the single most significant improvement in outcome for OS since the advent of chemotherapy in the 1960s.[2] Micro- metastasis are generally present at diagnosis and exist in the tumor microenvironment with tumor associated macrophages (TAMs). TAMs produce an anti-inflammatory environment and promote the progression of pulmonary metastasis. A strategy that can convert TAMs to the M1 or anticancer type, has the potential to eradicate micro-metastatic disease and prevent the development of pulmonary metastases, and ultimately improve survival for children with OS. The overall goal of this project is to prevent metastasis in children with OS. With support of the PCRTF, we have already developed and tested Macrophage-derived Engineered Vesicles (MEVs) from murine, bone marrow- derived monocytes and human monocytes. In our preliminary data, we demonstrate MEVs specifically interact with tumors in vivo and MEVs are able to convert TAMs to the M1 phenotype which led to anticancer activity. In an ovarian cancer animal model system we have demonstrated that both cisplatin loaded MEVs and empty MEVs have 1) no adverse effects after 10 weekly doses; 2) improved efficacy over saline control; 3) equivalent efficacy to free cisplatin. A confirmatory experiment in a pediatric osteosarcoma lung metastasis mouse model is underway. Given impressive preclinical activity, no toxicity and clear unmet medical need, our overarching goal of this proposal is to further advance MEVs as a therapeutic strategy. Our central hypothesis is that MEVs repolarize TAMs, which will eradicate micro-metastatic disease and ultimately prevent the development of metastasis and improve survival in osteosarcoma. Aim 1. Conduct a dose response study. In a proof of concept study using an ovarian cancer model (CAOV3 luciferase labeled in BALB/c scid mouse), the mean weekly MEV particle number and cisplatin dose administered was 4.21x1012 and 115 μg (4.6 ug/g), respectively. Aim1a. To determine the effect of MEV dose on clinical activity in a 143B osteosarcoma model, a three dose study will be conducted. A high (4.2x1021 particle number), intermediate (2.1 x1021 particle number) and low dose (1.1x1021 particle number) will be assessed. Mice will be dosed weekly for upto 10 doses and changes in tumor volume will be assessed by luciferase imaging. The primary comparison is the development of pulmonary metastasis between doses levels, however regression in tibial tumor burden will also be assessed. Aim 1b. Toxicity via weight, laboratory parameters and pathological assessment of mouse tumors. Assessment of dose response to MEVs is essential to establish future clinical dosing Aim 2. Transfer manufacturing process to a GMP facility. We have established and met production criteria for ~100 nM diameter EEVs from a variety of cell types with yields of ~ 5 x 1012 particles per batch, drug concentrations of ~125 ug/mL, a batch-to-batch CV% of less than 15% with a less than 10% failure rate. To support a phase 1 clinical trial, a critical step is to transfer manufacturing to a GMP facility with CLIA capability, which will be conducted at the University of Kentucky. Aim 2a. Since RAW cells are inexpensive and plentiful, initial manufacturing set-up will use RAW cells. Aim 2b. Next, apheresis collections from healthy volunteers will be obtained from commercial vendors. Complete preparation of MEVs from 5 normal volunteers that meet the acceptance criteria outlined above will be performed. Successful completion of these milestone will establish the GMP manufacturing process that will support our phase 1 clinical trial. Aim 3. The proposed studies will establish GMP manufacturing and determine the starting dose for our phase 1 clinical trial, which will establish the safe and effective dose of MEVs. Sentence about basic science aim We also anticipate EEVs have broad use as highly specific drug delivery nanoparticles as well as modulators of biological response for a variety of diseases and hypothesize specific delivery can both improve efficacy and eliminate adverse effects.
StatusNot started
Effective start/end date7/1/246/30/26

Funding

  • KY Cabinet for Health and Family Services: $250,000.00

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