The broader impact/commercial potential of this Small Business Innovation Research (SBIR) Phase I project involves creation of a new, immune-cell-based treatment to address the unmet physical and psychological health needs of women with locally advanced (Stage III) breast cancer at high risk for relapse following standard-of-care surgery and drug therapy. Called cancer sentinels, these living drugs are made from patient blood-derived B-cells that have been isolated, chemically activated, and genetically modified to selectively seek and destroy residual breast cancer cells before they form detectable tumors and spread to vital organs. Cure is dependent on early detection and cancer cell elimination prior to distant spread. These engineered therapeutics may promote the destruction of breast cancer cells in multiple ways, including activation of immune system and the secretion of cancer-killing antibodies. Additional solid tumor cancer types, such as colorectal cancer, lung cancer, and ovarian cancer may also be addressable by future cancer sentinel products. In total, greater than 200,000 American cancer patients each year may benefit. This Small Business Innovation Research (SBIR) Phase I project addresses unmet needs of nearly 50,000 American women annually who are subjected to anxiety, fear, and lifestyle disruption because of newly diagnosed, locally advanced breast cancer. Emotional toxicity, beginning at cancer diagnosis, tends to peak during standard watch and wait cancer surveillance and the relapse uncertainty that follows initial surgical resection and post-surgery adjuvant therapy. This project combines the natural and unique antigen binding, lymph node-homing, antigen presentation, protein secretion, T-cell co-stimulation, and immune memory capabilities of human B-cells with large-cargo, non-viral, CRISPR/Cas9 and homology-mediated end joining-based genome editing techniques, to create cancer sentinels. Cancer sentinels are intended to destroy residual and relapsed breast cancer cells by locally secreting engineered anti-cancer antibodies and/or cytokines at the time of minimal residual cancer and prior to distant metastasis. To achieve such a multi-functional B-cell drug, autologous blood-derived B-cells will be genetically modified to express surface B-cell receptors (BCRs) with affinity for specific tumor-associated antigens (TAAs). Engineered BCR binding to TAAs may trigger local secretion of the engineered anti-cancer response molecules. Detection of these response molecules in the blood may also serve as a biomarker and alert physicians to the presence of residual cancer.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.
