The artificial lymph node, which is a small sac embedded under the skin, contains key components of the immune system and is designed to play a crucial role in activating T-cells, the body's primary defenders against infections and abnormal cells. Lymph nodes, scattered across areas like the neck, armpits, and groin, serve as a link in alerting the immune system. These nodes serve a vital role in curbing infections and signaling potential threats throughout the body.

Natalie Livingston, Ph.D., the study's first author and a postdoctoral researcher at Massachusetts General Hospital, explains: “T-cells often lie dormant within lymph nodes, simply waiting for the right moment to attack infections or abnormal tissues. Unfortunately, cancer has learned to exploit this dormancy. That’s where this innovative artificial lymph node steps in — it reactivates the dormant T-cells to attack cancer cells.”

To build this artificial node, the scientists employed hyaluronic acid, a substance found in cosmetics and present naturally in the body’s skin and joints. Hyaluronic acid has numerous applications, often playing a role in biodegradable implants like wound healing patches. Johns Hopkins scientists, led by Jonathan Schneck, M.D., Ph.D., had shown previously that hyaluronic acid can enhance T-cell activation, making it an integral part of this synthetic node.

In their latest work, the research team layered this hyaluronic acid foundation with molecules like MHC (major histocompatibility complex) and HLA (human histocompatibility antigen), both of which are equipped with the ability to activate T-cells, while additional cancer-associated antigens were incorporated to “educate” the T-cells on what to target specifically.

"Our use of antibodies in the lymph node allows us to strategically direct what the T-cells should search for,” Livingston adds. The resulting structure is roughly 150 microns wide, approximately twice the width of a human hair — small enough to stay embedded under the skin but sizable enough to avoid being flushed away in the bloodstream.

Schneck explains how this approach holds an edge over other therapies like CAR-T, which typically involve extracting and modifying T-cells outside the body. "With our method," Schneck notes, "the T-cells get activated by the node directly inside the body, allowing them to circulate and attack cancer cells anywhere without the extra manufacturing steps associated with CAR-T therapy."

The research, led by Schneck and Hai-Quan Mao, Ph.D., director of the NanoBioTechnology Institute at Johns Hopkins, demonstrated the effectiveness of the artificial lymph node on mice implanted with melanoma or colon cancer. Six days after tumor implantation, mice received injections containing the artificial lymph node and T-cells.

A comparison was made between various groups, including mice receiving only the artificial node, those injected with just T-cells, and patients treated with a combination of T-cells and an immunotherapy drug called anti-PD-1. Remarkably, the group given both the artificial node, T-cells, and anti-PD-1 therapy showed the longest survival (three mice out of seven were still alive at 33 days), and their tumor growth was significantly slowed, with tumors taking an additional five to ten days to double in size compared to other groups.

The artificial node not only heightened the activity of T-cells but also attracted other immune cells to create a highly immunologically active environment. In fact, when injected alongside the node, the T-cell population in the mice multiplied by a factor of nine.

Livingston notes the distinction of this approach from cancer vaccines, which typically rely on dendritic cells to teach T-cells their targets. Cancer patients sometimes have malfunctioning dendritic cells, making this direct activation of T-cells by the artificial node even more significant, as it bypasses this common problem.

Going forward, the research team hopes to fine-tune the artificial lymph node by adding more signaling molecules, aiming to draw even more immune cells into the node, further amplifying the immune response.

“We’ve combined materials science with immunology to design a potential therapeutic that functions as a living drug, forming its own immune community within the body,” Schneck concludes.

The team has applied for a patent related to this cutting-edge technology, which has been supported by funding from numerous organizations, including the National Institutes of Health (R01EB029341, R21CA185819, P41EB028239, T32AI007417), the National Science Foundation, as well as several fellowships and awards from institutions such as the ARCS Foundation, the Siebel Foundation, and the Natural Sciences and Engineering Research Council of Canada.

Several other contributors from Johns Hopkins also played a crucial role in this research, including John Hickey, Hajin Sim, Sebastian Salathe, Joseph Choy, Jiayuan Kong, Aliyah Silver, Jessica Stelzel, Mary Omotoso, Shuyi Li, Worarat Chaisawangwong, Sayantika Roy, Emily Ariail, Mara Lanis, Pratibha Pradeep, Joan Glick Bieler, Savannah Est Witte, Elissa Leonard, Joshua Doloff, and Jamie Spangler.

DOI: 10.1002/adma.202310043