Turning Breast Cancer Cells Against Themselves as the Next-Generation Immunotherapy
Abstract
Scientific Objective: Our goal is to develop a transformative new strategy – Synthetic Tumor Recruited Immuno-Cellular Therapy (STRICT) – for treating triple-negative breast cancer (TNBC). STRICT forces tumors to recruit immune cells that kill primary tumors and metastasis. To achieve this goal, we will design artificial gene circuits activated explicitly in TNBC cells. These gene circuits will command TNBC cells to secrete immune modulators that attract immune cells to target the tumors for destruction. This effect should also induce long-term immune memory against cancer relapses. Here, we will develop, optimize, and validate the effectiveness of STRICT within in vitro and in vivo mouse models of TNBC. Rationale: The immune system has been harnessed to treat a variety of blood cancers, including acute leukemia and multiple myeloma, via cell-based therapies. These strategies require isolation, engineering, and expansion of immune cells from each patient, which is expensive and labor-intensive. Furthermore, these approaches have not yet been applied successfully against TNBC, which poses additional therapeutic challenges due to the heterogeneity found in the tumors. Thus, there is an urgent need for novel, safe, and effective therapies. We aim to develop novel therapies that act from within tumors to recruit and activate immune cells into tumors – a Trojan horse approach. Specifically, we will design genetic circuits that can be delivered locally or systemically, sense when they are inside cancer cells, and respond by producing combinations of complementary immune modulators from within tumors. These immune modulators shall recruit immune cells into the tumors, thus harnessing the immune system to target TNBC and establishing long-lasting protection against metastasis and recurrent cancer. STRICT can be modulated and shut off if needed, thus providing controllable safety switches. Furthermore, STRICT does not require custom cellular engineering for every patient, thus enabling greater patient access and reduced burden on health care infrastructure. STRICT can also be used with other cancer therapies to achieve enhanced efficacy. Aims: In Aim 1, we will engineer synthetic gene circuits to specifically express immunomodulators within tumors to recruit immune cells to kill tumors. We shall validate the effectiveness of these gene circuits in vitro in TNBC models. We will also optimize STRICT to target heterogeneous tumors. In Aim 2, we will identify the optimal therapeutic output combination that confers the strongest efficacy. We will also determine the minimal percentage of cancer cells that need to be targeted by the synthetic gene circuits to achieve therapeutic efficacy in mouse models of TNBC. In Aim 3, we will elucidate the immune response triggered by STRICT. We will also test the ability of STRICT to eliminate primary and metastatic TNBCs in fully immunocompetent mice. Furthermore, we will measure whether STRICT can trigger immune memory to prevent tumor relapses. This work will establish key parameters needed for successful immunotherapy against TNBC and enable the optimization of designs for future preclinical and clinical trials. Overarching Challenges: We aim to address two overarching challenges: (1) revolutionize treatment regimens by replacing them with ones that are more effective, less toxic, and impact survival; and (2) eliminate the mortality associated with metastatic breast cancer. What types of patients will be helped and how? This work will benefit TNBC patients, especially ones with metastatic disease or cancer relapse, with a new and potentially powerful therapy. What are potential clinical applications, benefits, and risks? Our strategy has the potential to become a new clinical therapy for TNBC. The potential benefits of this technology include providing highly effective treatment for metastatic TNBC and protection against future relapse. The potential risks of this technology in
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310031
Entities
People
- Ming-ru Wu
Organizations
- Dana–Farber Cancer Institute
- United States Army