Transforming Triple-Negative Breast Cancer Treatment Through Intratumoral Immunotherapy via Nanofluidic Drug-Eluting Seed
Abstract
Accounting for 15%-20% of all breast cancers, triple-negative breast cancers (TNBC) are challenging to treat due to high tendency to metastasize and recur after standard treatment. The standard treatment involves administration of anticancer drugs intravenously, which results in the drug being delivered throughout the entire body. Only a small amount of drug actually reaches the tumor, while healthy cells and organs are exposed to the toxic drug. As a result, patients suffer from adverse side effects, some of which are life-threatening and persist lifelong despite stopping treatment. A prime example of this scenario is immunotherapy, which was recently approved for TNBC patients. Immunotherapy works by triggering a person’s immune system to attack cancer cells. Unfortunately, this represents a double-edged sword, as whole-body triggering of the immune system can also lead to activation of the immune cells to attack healthy cells and organs, leading to auto-immune and inflammatory side effects and off-target toxicities. The issue of immunotherapy-induced toxicity is further exacerbated due to the need for repeated drug dosing to generate sufficient cancer-fighting immune response. These issues emphasize that current immunotherapy delivery strategies require a complete change of direction to achieve their full potential with negligible toxicity. To address this, we propose a transformative local immunotherapy delivery strategy that combines the emerging fields of nanotechnology and immunotherapy. Addressing the Department of Defense’s breast cancer research objectives, the overarching goal of the proposed project is to revolutionize treatment regimens by replacing them with ones that are more effective, less toxic and impact survival. With the goal of maximizing immunotherapy treatment efficacy for patients without side effects, we developed a tiny nanodevice called nanofluidic drug-eluting seed. The seed is inserted in the tumor via a minimally invasive needle procedure already used in clinical practice. Drug release occurs autonomously, eliminating the need for using intravenous catheters, pumps or ports, repeated injections or physician intervention. Upon insertion, the seed acts as a “Trojan horse” and constantly release immunotherapy into the tumor, long term, thus locally triggering an army of anti-cancer immune cells to kill cancer, both on site and around the body (metastases). In other words, using our immunotherapy-releasing seed, we leverage the tumor to instruct the immune cells to recognize and kill cancer. Then, the immune cells will circulate the body to find and destroy cancerous cells, including at the metastatic sites. Clinically, we envision our seed to be inserted inside a tumor, to activate the immune system, and finally removed during surgical excision of the tumor mass. In this proposal, we aim to evaluate the effect of local immunotherapy delivery through our device on controlling tumor growth, preventing metastasis, eliminating toxicity and prolonging survival in two relevant and established rodent models of TNBC. To fully elucidate the function of our approach, we will also evaluate the distribution of the drug in the tumor and body when delivered in a continuous manner directly in the tumor, as well as assess its effect on modulating the immune milieu of the tumor site. Our device represents a transformation in the way cancer therapeutics are administered to patients. It could significantly improve treatment outcome and patients’ quality of life by maximizing drug exposure in the tumor, minimizing side effects, and eliminating the need for hospital visits for repeated infusions. Moreover, our intratumoral strategy uses small amounts of drugs, which combined with inexpensive cost of large-scale fabrication of the device render it cost-effective to maximize therapeutic reach regardless of socioeconomic status. If successfully validated in this study, our intratumoral drug de
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Mar 10, 2021
- Source ID
- W81XWH2010600
Entities
People
- Alessandro Grattoni
Organizations
- Houston Methodist Research Institute
- United States Army