Tumor Immunotherapy by Gene-Circuit Engineered Response (TIGER) for Neuroendocrine Prostate Cancer
Abstract
Scientific Objective: Our goal is to develop a transformative new strategy - Tumor Immunotherapy by Gene- circuit Engineered Response (TIGER) for treating neuroendocrine prostate cancer (NEPC). NEPC is the most aggressive subtype of prostate cancer and usually occurs during hormonal therapy. TIGER forces tumors to recruit immune cells to kill primary tumors and metastasis. To achieve this goal, we will design artificial gene circuits activated explicitly in NEPC cells. These gene circuits will command NEPC cells to secrete immune modulators that attract immune cells to target the tumors for destruction. This effect will also induce 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 NEPC. 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 NEPC, 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 will condition the tumor microenvironment to favor immune response, recruit immune cells into the tumors, thus harnessing the immune system to target NEPC and establishing long-lasting protection against metastasis and recurrent cancer. 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. Aims: In Aim 1, we will engineer synthetic gene circuits to specifically express immunomodulators within tumors to recruit immune cells to kill tumors. We will validate the effectiveness of these gene circuits in vitro in NEPC patient-derived organoid models. We will also optimize TIGER 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 TIGER to achieve therapeutic efficacy in mouse models of NEPC. In Aim 3, we will elucidate the immune response triggered by TIGER. We will also test the ability of TIGER to eliminate primary and metastatic NEPCs in fully immunocompetent mice. Furthermore, we will optimize the capacity of TIGER to trigger immune memory to prevent tumor relapses. This work will establish key parameters needed for successful immunotherapy against NEPC and enable the optimization of designs for future preclinical and clinical trials. Overarching Challenges: We aim to address the following FY22 PCRP overarching challenge - develop treatments that improve outcomes for men with lethal prostate cancer. What Types of Patients will be Helped and How? This work will benefit NEPC and castration-resistant prostate cancer 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 NEPC. The potential benefits of this technology include providin
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310152
Entities
People
- Ming-ru Wu
Organizations
- Dana–Farber Cancer Institute
- United States Army