Undergraduate Research Fellow, Mikhail Shapiro Laboratory at Caltech
Mikhail Shapiro's lab develops biomolecular technologies to noninvasively image and control cells in the human body. During my undergrad at Caltech, I worked on engineering these tools to better study and treat solid tumors and other forms of cancer.
Acoustic Remote Control of Bacterial Immunotherapy
Cell-based immunotherapies (ie CAR T-cells) have made headlines as a promising form of cancer treatment that relies on engineering our own immune cells to better target tumors within the body. However, these modes of therapy are often limited in their ability to treat solid tumors, largely because of their hypoxic and immune-privileged environments.
Fortunately for us, certain strains of E coli bacteria can actually home to and thrive in low-oxygen, immune-privileged regions of the body, making them promising agents to reshape tumor microenvironments and ultimately elicit a cancer-targeting response. However, prior studies have struggled with on-target, off-tumor homing of bacteria that can lead to undesirable systemic immune responses and damage to healthy tissues. It was important for us to be able to figure out a way to modulate bacterial activity and communicate with them to only activate their engineered therapeutic response only within the context of a tumor.
One mechanism of communicating with cells deep within the body is high-intensity focused ultrasound (HIFU), which is already being used in the clinic to heat local areas of the body with high spatiotemporal precision. We engineered bacteria to release therapeutic molecules in a heat-dependent manner, so that they would only elicit a therapeutic effect in the local tumor microenvionment heated with HIFU noninvasively.
Ultimately, we engineered a strain of E coli to release anti-CTLA-4 and anti-PD-L1 nanobodies that act as immune checkpoint inhibitors, and demonstrated a HIFU-dependent therapeutic response in mice models. Our results are published in Nature Communications.
Visualizing Hypoxia Deep Within the Body
I functionalized a genetically encodable MRI contrast agent as an in-vivo hypoxia sensor for glioblastoma cells. Many drugs that are being developed for the treatment of solid tumors are sensitive to environmental oxygen levels, which can present challenges in making the drugs effective within hypoxic tumor microenvironments. The effect of local hypoxia is often difficult to quantify because of the inability to easily measure oxygen levels within a solid tumor without disturbing the local tumor microenvironment. To address this limitation, we engineered a cell-based hypoxia sensor for MRI, a widely used imaging modality, such that the strength of the MRI signal could be used to estimate the oxygen level in the cellular environment.
Ideally, these engineered glioblastoma cells can be used as a research tool in better understanding the complex tumor microenvironment in a noninvasive manner, and also assessing anti-angiogenic and anti-vasculogenic therapies as a function of oxygen levels in the tumor.