Engineer Synthetic Tumor Recruited Immunocellular Therapy (STRICT)
Abstract
Objective: Our central objective is to eradicate prostate cancer. Our strategy, Synthetic Tumor Recruited Immuno-Cellular Therapy (STRICT), 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, STRICT will be effective against cancer relapse. Rationale: Metastatic disease is the main cause of prostate cancer mortality and 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. Thus, there is a strong need for new immunotherapies that are effective against high-risk, metastatic, or recurring disease and that are highly specific against cancer while sparing normal cells. 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, such as Surface T-cell Engagers (STEs) and other molecules that can recruit and activate immune cells. Human immune cells (T cells), recruited 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: STRICT 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. STRICT can be further optimized by integrating it with other cancer 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 STRICT to eliminate metastatic prostate cancer via systemic administration. We will determine whether STRICT prevents tumor relapse via long-term immune memory, set key parameters for successful immunotherapy, and optimize designs in preparation for future preclinical and clinical trials. Who Will Be Helped and How? This work will benefit prostate cancer patients, especially those with high-risk, metastatic, or relapsing disease, with a new and potentially powerful therapy, to be used alone or with other therapies. STRICT provides a platform for building effective and highly targeted treatments against difficult-to-treat prostate cancers. Potential Clinical Applications, Benefits, and Risks: STRICT has the potential to become a new therapy for prostate cancer. Benefits include highly effective treatments for metastatic cancer and long-lasting protection against cancer relapse. Risks include the difficulty of finding a suitable delivery vehicle. We have outlined a comprehensive plan to minimize risk via alternative strategies. Furthermore, our lab has deep expertise in designing synth
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 31, 2017
- Source ID
- W81XWH1610565
Entities
People
- Timothy K. Lu
Organizations
- Harvard University
- United States Army