For years, CAR T-cell therapy has revolutionized the treatment of blood cancers like leukemia. However, its effectiveness against solid tumors—the vast majority of cancer types—has remained elusive. Now, researchers have achieved a significant breakthrough: “weaponized” CAR T-cells have completely eradicated large prostate tumors in mice, fueling hopes for a broader application in treating various cancers.
The Challenge of Solid Tumors
Our immune system naturally defends us by identifying and eliminating cancerous cells. This process relies on T-cells, a type of immune cell that hunts down cells with mutant proteins on their surface, much like antibodies bind to foreign invaders. While promising, this immune response isn’t always triggered in all cancers.
In the 1980s, scientists began exploring the potential to genetically modify T-cells, leading to the development of CAR T-cells. This involves adding a gene for a synthetic receptor, called a chimeric antigen receptor, allowing them to precisely target and attack cancer cells. While CAR T-cell therapy can be curative in some individuals, it’s not without risks, and recent advancements, like CRISPR gene editing, are continuously being implemented to improve their efficacy.
Despite these improvements, CAR T-cells have largely failed to combat solid tumors due to two primary hurdles:
- Tumor Heterogeneity: Solid tumor cells often exhibit diversity, lacking a uniform mutant protein on their surfaces.
- Immune Suppression: Solid tumors employ tactics to evade immune attacks, such as releasing signals that essentially tell the immune system to “leave me alone.”
Localizing the Attack: A New Approach
To overcome these challenges, researchers have focused on “weaponizing” CAR T-cells. One strategy involves equipping them with potent immune-stimulating proteins, such as interleukin 12. However, previous attempts using this approach proved too powerful, triggering an excessive immune response that damaged healthy tissues.
Jun Ishihara at Imperial College London and his team have devised a clever solution to localize interleukin 12 specifically to tumors. They fused interleukin 12 with a fragment of a protein that binds to collagen, a structural protein. This collagen-binding protein normally aids in healing by targeting collagen exposed in wounded blood vessels. Notably, tumors also exhibit exposed collagen, creating a targetable site.
The team further engineered CAR T-cells so that the fused protein is produced only after these T-cells bind to a mutant protein found on some prostate cancers. Once released within the tumor, the fused protein targets and remains localized to collagen, effectively amplifying the “Attack! Attack!” signal.
Remarkable Results in Mice
In laboratory tests, this innovative treatment completely eliminated large prostate tumors in four out of five mice. Crucially, when these mice were later exposed to cancerous cells, they did not develop new tumors, indicating that the CAR T-cells had generated a robust and lasting immune response.
Surprisingly, the mice did not require the traditional preconditioning chemotherapy used to deplete existing immune cells and “make room” for the engineered CAR T-cells. This eliminates potential side effects like fertility issues associated with chemotherapy. Ishihara’s team hopes to initiate clinical trials in humans within two years.
Expert Perspective
“I do think this is a promising approach that should be tested clinically,” states Steven Albelda at the University of Pennsylvania. Albelda notes that numerous other research groups are also exploring methods to target interleukin 12 to tumors, and some have already achieved encouraging outcomes.
This innovative approach offers a potentially safer and more effective way to harness the power of the immune system to fight solid tumors, bringing a new hope for cancer treatment.
This research represents a significant stride forward in cancer immunotherapy, potentially paving the way for a broader range of effective treatments against various solid tumors and improving outcomes for patients
