Drugging the Undruggable: Programming Ovarian Cancer Cells as the Next-Generation Immunotherapy
Abstract
Scientific Objective: Our goal is to develop a transformative new strategy—Tumor Immunotherapy by Gene-circuit Engineered Response (TIGER) for ovarian cancer. Ovarian cancer is the most lethal gynecological malignancy in the USA and usually relapses after standard treatment. TIGER forces tumors to recruit immune cells to kill primary tumors and metastasis. To achieve this goal, we have designed artificial gene circuits activated explicitly in ovarian cancer cells. These gene circuits will command ovarian cancer cells to secrete immune modulators that attract immune cells to target the tumors for destruction. This effect will also in-duce long-term immune memory against tumor relapses. Here, we will develop, optimize, and validate the effectiveness of TIGER within in vitro and in vivo mouse models of ovarian cancer. 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 ovarian cancer, which poses additional therapeutic challenges due to the tumor heterogeneity and immune suppressive microenvironment. 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— 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 will condition the tumor microenvironment to favor immune response and recruit immune cells into the tumors, thus harnessing the immune system to target primary tumors and establishing long-lasting protection against metastasis and recurrence. TIGER can be modulated and shut off if needed, thus providing controllable safety switches. Furthermore, TIGER does not require custom cellular engineering for every patient, thus enabling greater patient access and reduced burden on healthcare infrastructure. TIGER can also be used with other cancer therapies to achieve enhanced efficacy. Specific Aims: In Aim 1, 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 TIGER to achieve therapeutic efficacy in various clinically-relevant mouse models. In Aim 2, we will elucidate the immune response triggered by TIGER. Furthermore, we will optimize the capacity of TIGER to trigger epitope spreading that counteracts tumor heterogeneity and immune memory to prevent tumor relapses. This work will establish key parameters for successful immunotherapy against ovarian cancer and enable the optimization of designs for future preclinical and clinical trials. Area of Emphasis: We aim to address the following FY22 OCRP Area of Emphasis: develop novel therapeutic strategies for treatment and prevention. Which Individuals Will It Help and How Will It Help Them? This work will benefit ovarian cancer patients, especially ones with metastatic or recurrent diseases, with a new and potentially powerful and long-lasting therapy. What Are the Potential Clinical Applications, Benefits, and Risks? Our strategy can potentially become a new clinical therapy for ovarian cancer. The potential benefits of this technology include providing highly effective treatment for ovarian cancer and protection against future relapse. The potential risks of this technology include the challenge of targeting heterogeneous solid tumors, although we have outlined a comprehensive plan to minimize this risk with a set of alternative strategies. What
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310455
Entities
People
- Ming-ru Wu
Organizations
- Dana–Farber Cancer Institute
- United States Army