In vivo transdermal generation of CD33 CAR T-cells towards acute myeloid leukemia
Pediatric acute myeloid leukemia (AML) is the second most common pediatric leukemia, with treatments still based on intense, conventional chemotherapy and overall survival remaining below 70%. Recently, therapeutic research has explored the engineering of a patient’s own immune cells to target unique AML cell surface markers. However to manufacture these therapies immune cells must be collected from patients whose immune system has been depleted by multiple rounds of chemotherapy. To overcome this challenge, research has been focused on the engineering of a patient’s immune cells while still inside their body. To do this, a series of nanotechnology tools need to be developed. Firstly, delivery vehicles known as lipid nanoparticles must be optimized to hold immune cell engineering cargo. To ensure that these cargo are delivered to immune cells and no other cell types, we must also add immune cell targeting capabilities to the outside of our lipid nanoparticles. Lastly, the type of immune cells we target and how we access them will be crucial to the success of our proposed research. The skin serves as our first line of defense against infection, containing a plethora of immune cells. To access the immune cells in the skin, we will load our nanoparticles into microneedle patches. As microneedle patches do not reach pain receptors in the skin, they will provide virtually pain-free nanoparticle delivery, establishing a safe, effective way of engineering immune cells in the body.
Project Goal:
Cellular therapies that engineer a patient’s own immune cells to target cancer have revolutionized the treatment of some leukemias and lymphomas. Though currently manufactured externally, next generation therapies focus on engineering immune cells within a patient’s body. We propose that targeting pediatric acute myeloid leukemia (AML) using similar therapies will improve clinical outcomes for patients. To design the tools required to facilitate these therapies, our research will focus on three key components. Inspired by the latest COVID19 vaccines, we will optimize a nanoparticle delivery vehicle to carry our immune cell engineering cargo, maintaining high delivery efficiency and the protection of cargo from degradation. To ensure our nanoparticles are delivered to immune cells while sparing other cells, we will add targeting capabilities to the surface of our nanoparticles and compare their specificity against other cell types. Lastly, we will take a unique approach to accessing a patient’s immune cells and delivering our nanoparticles. We will design and optimize a microneedle patch, similar to a pimple patch, loaded with nanoparticles to access immune cells present in the skin. We will test our ability to access and engineer these immune cells and evaluate their effectiveness in eliminating AML cells. The proposed research will facilitate the safe and effective engineering of AML targeting immune cells in the body
