Context-Dependent CAR Activation: Engineering Mechanosensitive T Cells to Treat Solid Tumor Metastases
Abstract
Colorectal cancer is a common disease among Veterans and the third-most common cancer nationwide. The colorectal cancer incidence rate is skewed to current Veterans (90% of those diagnosed are over 55 years of age). In addition, colorectal cancer has a 25% higher incidence in males aged between 50 and 70 years old compared to its incidence in females. Given that current Veterans are predominantly male due to historic reasons, colorectal cancer therefore disproportionally affects current US Veterans and their beneficiaries. Of particular clinical challenge is the metastatic colorectal cancer, which has only a 13% 5-year survival rate. Metastatic colorectal cancer is not amenable to conventional treatments such as chemotherapy or surgery. Even with advances in cancer immunotherapy, using combination of conventional treatments with monoclonal antibodies has only increased the median survival rates by several months. The recent Chimeric Antigen Receptor (CAR)-T cell therapy has gained major success in treating hematological cancers. CAR-T cells work by activating the T cell response to kill cancer cells upon binding to specific cancer antigens. However, CAR-T cells encounter many hurdles when it comes to attacking solid tumors and their metastases. Of particular challenge is their “on-target/off-tumor” cytotoxicity as CAR-T cells can be activated at non-tumor sites where low-levels of target antigens are often expressed. Numerous recent clinical trials of using CAR-T cells to treat solid tumors have been halted because some patients died due to their strong toxicity. In the proposed work, we aim to improve tumor-targeting specificity of CAR-T cells and reduce their toxicity. We will engineer CAR-T cells to respond not only to cancer antigens (carcinoembryogenic antigen for colorectal cancer) but also to the unique tumor microenvironment physical properties. Our rationale is based on the recent discoveries that (1) solid tumor and metastatic tissues (including metastatic colorectal cancer) tend to be stiffer than healthy normal tissues, and (2) T cells sense mechano-environmental cues (e.g., forces, stiffness) and transduce that information to downstream functions such as activation or gene expression. Our approach therefore allows CAR-T cells to be activated only at the tumor sites but not healthy tissues. In our research strategy, we will first construct mechano-responsive CAR-T cells by engineering them with stiffness-sensing promoters. We will then test their efficacy and toxicity using stiffness-tunable hydrogel system in vitro and colorectal cancer animal models in vivo. Our proposed work aligns perfectly with Fiscal Year 2016 (FY16) Peer Reviewed Cancer Research Program Military Relevance Focus Areas: Colorectal Cancer and Immunotherapy. Additionally, improvements in targeting CAR-T cells will benefit FY16 Military Relevance Focus Areas in closing gaps in cancer treatment and survivorship by developing new technologies to treat metastatic colorectal cancer, a disease that disproportionately impacts military Service members, Veterans, and their beneficiaries. Our new CAR-T therapy will be the first of its kind that target both cancer cells and the microenvironment biophysical cues, and has the potential to lead to more effective therapies for metastatic cancer that lack severe side effects. It is our hope that the proposed therapy will improve survival and even lead to an enduring cure for the people living with metastatic colorectal cancer and even other types of solid cancer metastasis in the future. This Idea Award will pave the way to initiate a clinical trial to test our novel CAR-T therapy in Veteran patients diagnosed with metastatic colorectal cancer in the short term (within 3-5 years). In the long term (5-10 years), our therapy, if successful, could be applied to current Veterans affected by metastatic colorectal cancer.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Oct 29, 2018
- Source ID
- W81XWH1710522
Entities
People
- Weian Zhao
Organizations
- Naval Information Warfare Center Pacific
- United States Army