Supercharging the Body’s Defense System
Immunotherapy has provided a powerful array of tools for fighting a variety of diseases using the body’s own immune system. The first documented immunotherapeutic techniques date back some 3,000 years, with significant leaps forward in the late nineteenth century, the mid-twentieth century, then again in 2018, when James P. Allison and Tasuko Honjo won the Nobel Prize in Physiology or Medicine for their discovery of treating cancer by inhibition of negative immune regulation.
Adoptive cell therapy using immunotherapy treatments for cancer have been particularly exciting. Chimeric antigen receptor technologies have been one of the most significant breakthroughs in immunotherapy, particularly when it comes to cancers of the blood. However, the effectiveness of CAR immunotherapies is limited when it comes to solid tumors. In addition, these treatments come with certain risks to the patient, for example cytokine release syndrome, and immune effector cell-associated neurotoxicity syndrome, which are both potentially life-threatening.
Treatments involving lab engineered CAR-iNKT cells (or killer T-cells) have been more promising when it comes to treating solid tumors, however the effectiveness of the treatment can be hampered by the cells’ loss of potency once the treatment enters the body.
A team at UCLA has developed an implant that shows promise in mitigating that loss of potency. It may also help to fight cancer cells in other parts of the body. In addition, the team’s system has been shown to avoid the risk of cytokine release syndrome, making treatments potentially safer.
The Problem
Studies involving chimeric antigen receptor-invariant natural killer T-cells (CAR-iNKT cells) have shown promise in fighting cancer, particularly when it comes to solid tumors that have proven resistant to traditional CAR-T therapy. The problem is that lab-engineered CAR-iNKT cells often lose potency after entering the patient’s body. And this can negatively impact the effectiveness of the treatment.
The Study
A team at UCLA has developed an implantable system that acts like a charging station for the lab engineered CAR-iNKT cells. Once the device is implanted near a tumor, it attracts the killer T-cells that have been engineered to recognize and fight cancer. It then activates the cells, giving them an extra power boost, and helps them to multiply. The researchers called this “recruit, activate, and expand.”
The system depends on biometric particles designed to mimic the activation signals for iNKT cells.
One of the study’s co-leaders, Song Li, chancellor’s professor of bioengineering at the UCLA Samueli School of Engineering, explains it this way.
“These engineered microparticles are where CAR-iNKT cells recharge and switch back into attack mode…Instead of delivering a one-time boost, the device provides sustained signals that help the cells stay active, multiply and form long-term memory.”
The engineered microparticles reactivate the CAR-iNKT cells using a molecule called TCR antigen. The CAR-iNKT cells connect to the TCR antigen, which sets off a series of molecular signals that activate the cells and send them back out to destroy cancer cells.
The particles also contain capsules filled with IL-15, a signaling protein that promotes cell growth.
Says another co-leader of the study, Lili Yang, professor of Microbiology, Immunology and Molecular Genetics at UCLA, “This approach significantly improves the durability and effectiveness of CAR-iNKT cell responses in both solid tumor and systemic blood cancer models, offering a new strategy to strengthen cell-based cancer therapies and expand their clinical potential.”
Yan-Ruide Li, a postdoctoral scholar of microbiology, immunology, and molecular genetics at UCLA, and the first author of the study, likens the process to plugging your phone into a charging cable, saying, “In this case, the CAR-iNKT cells connect to the TCR antigen, which sets off a series of molecular signals that activate them, sending them back out to destroy cancer cells.”
The device had an additional unexpected benefit. The team’s experiments showed that once reactivated, the immune cells entered the bloodstream and eliminated cancer cells in other locations, as well. This systemic, anti-tumour immune activity is a new development in engineered cell therapies. Future treatments may no longer be limited to controlling a local tumor. Some believe this new technology could lead to comprehensive cancer elimination throughout the body,
The process was far from simple. In order for the technology to be successful, it had to be finely tuned. Stimulating the CAR-iNKT cells too much could wear them out. On the other hand, too little stimulation wouldn’t prevent the engineered cells from losing function. In order to get the balance just right, the researchers optimized the strength of the activation signals coming from the device, as well as the release of the growth-supporting proteins. Optimizing the design of the materials also helped to maintain a balanced immune response.
Researchers also had to keep the activation signals localized. Earlier treatments that involved circulating immune activating drugs throughout the body often caused harmful side effects. The device in the study, however, concentrated the activation signals at the site of the implant, near the tumor. This system therefore supported the engineered immune cells while limiting exposure to them elsewhere in the body.
The system showed strong compatibility with the biological systems in animal studies, with minimal adverse effects. In particular, the system avoids systemic cytokine release syndrome, a common and potentially dangerous side effect of current immunotherapies. This means the possibility of safer treatments for patients, as well as the possibility of combining different types of treatments, such as those involving checkpoint inhibitors or chemotherapy.
The study focussed on immunotherapy against human melanoma and lymphoma samples, but the team is investigating how the technology could be used for immunotherapy against other types of cancer.
Future Promise
The researchers are planning further testing. If successful, the technology could possibly be adapted to support other kinds of engineered immune cells. This, in turn, could lead to treatments for different types of cancers, or even different diseases beyond cancer. Some possibilities include personalized immunotherapy regimens, portable treatments, and dissolvable versions that could be used to treat illness non-invasively.