Tumor Immunotherapy by Gene-Circuit Recruited Immunomodulatory Systems (TIGRIS) for Prostate Cancer
Abstract
Objective: Our central objective is to eradicate prostate cancer. Our strategy, Tumor Immunotherapy by Gene-circuit Recruited Immunomodulatory Systems (TIGRIS), makes use of the body s own immune system to kill primary tumors and metastases. Our artificial gene circuits will be specifically activated in prostate cancer cells. These circuits will co-opt the cancer cells to attract immune cells (T cells), which will destroy the tumors. By inducing long-term immune memory, TIGRIS will be effective against cancer relapse. Rationale: Metastatic disease is the main cause of prostate cancer mortality; there is an urgent need for novel, safe, and effective therapies. Existing immunotherapies often work by distinguishing cancer cells from normal ones based on cancer-cell-specific signatures on their cell surfaces. However, these signatures are hard to find for most tumors, thus limiting the applicability of immunotherapy. Furthermore, current T-cell immunotherapy requires labor-intensive and costly engineering of patient-specific cells for each individual patient. We intend to develop novel therapies in which T cells (part of the patient s immune system) are recruited to kill cancer cells based on intracellular signatures that are easier to identify and target than extracellular ones. Highly engineered DNA sequences (gene circuits), delivered systemically, will be turned on only within cancer cells and not in normal cells. Cancer cells will respond to the activated gene circuit by producing immune-modulating proteins, principally Surface T-cell Engagers (STEs). Human immune cells (T cells), attracted by the STEs, will be brought into proximity with tumor cells, which then are killed. It is not only those cancer cells harboring the gene circuit that will be killed, TIGRIS will elicit an extended immune response, killing even those cancer cells that do not have the gene circuits and establishing long-lasting protection against metastases and recurrent cancer. Safety switches incorporated into the circuits will enable physicians to modulate the circuits or shut them off if needed. TIGRIS does not require custom engineering for every patient, enabling greater patient access and reducing the burden on healthcare infrastructure, and it can be combined with other therapies. Aim 1: We will engineer synthetic gene circuits to specifically display and express immune modulators in order to recruit T cells to kill tumors. We will validate the effectiveness of these gene circuits in in vitro prostate cancer models and determine the minimal number of cancer cells that need to receive the gene circuits to achieve therapeutic efficacy in mouse models of prostate cancer. Aim 2: We will test the ability of TIGRIS to eliminate metastatic prostate cancer via systemic administration. We will determine whether TIGRIS prevents tumor relapse via long-term immune memory, set key parameters for successful immunotherapy, and optimize designs for future preclinical and clinical trials. Career Goals in Prostate Cancer Research: My career goals are to harness the power of synthetic biology to create effective immunotherapies for incurable cancers, such as metastatic prostate cancer. Prof. Timothy Lu and Prof. Jianzhu Chen are my mentors for the proposed project. The Lu lab and the Chen lab have the complementary expertise essential for me to create a new generation of immunotherapy. Specifically, Prof. Lu s group has been at the forefront of engineering synthetic gene circuits in living cells. Prof. Chen s group has been the leader of prostate cancer immunotherapy and has developed advanced humanized mouse tumor models for studying immunotherapy. The expertise from both mentors, together with my expertise in tumor immunotherapy, will make me a future leader of prostate cancer research. Who Will Be Helped and How? This work will benefit prostate cancer patients, especially those with metastatic disease or cancer relapse, wit
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610452
Entities
People
- Ming-ru Wu
Organizations
- Harvard University
- United States Army