‘Enhanced’ CAR T-Cell Therapy Shows Potential in Treating Solid Tumors

CAR T cells, which are immune cells modified to attack cancer, have transformed blood cancer treatments, particularly for leukemia. However, they have struggled against solid tumors. Recently, “weaponized” CAR T cells have successfully eliminated large prostate tumors in mice, providing optimism for similar therapies in humans.

“The tumor is completely gone,” states Jun Ishihara from Imperial College London, marking a unique achievement in animal research.

Our immune system typically identifies and destroys many cancers early on. Cancer cells often display mutated proteins recognized by T cells, which seek to eliminate these threats using surface receptor proteins, functioning similarly to antibodies.

However, not every cancer incites an immune response. In the 1980s, scientists found a way to engineer T cells to target cancer more effectively by incorporating genes for chimeric antigen receptors, hence the term CAR T.

While CAR T cells have shown remarkable success in treating some blood cancers, they also carry significant risks. They are effective for some but not all patients, and ongoing enhancements are needed. The development of CRISPR gene editing facilitates further improvements to these therapies.

Despite advancements, CAR T therapies remain ineffective for most solid tumors due to two primary challenges: the vast heterogeneity of solid tumors—where not all cells present the same mutated proteins—and the tumors’ ability to evade immune responses by emitting “do not attack” signals.

Researchers have attempted to enhance CAR T cells by incorporating immune-boosting proteins like interleukin-12, but this has sometimes resulted in overwhelming immune responses that damage healthy tissues.

Ishihara and colleagues have pioneered a method to localize interleukin-12 specifically to tumors. By fusing interleukin-12 to a protein that binds collagen, which is prevalent in tumors, they engineered it to target the exposed collagen found in both wounds and tumors. “Tumors are rich in collagen and are dense because of it,” Ishihara noted.

The modified CAR T cells produce this fusion protein when they bind to the mutated proteins present in certain prostate cancers. Once released, the fusion protein attaches to the tumor’s collagen, effectively signaling the immune system to launch an attack.

Trial results were promising, as the treatment eradicated 80% of large prostate tumors in the test mice. Additionally, when exposed to cancer cells afterward, no new tumors formed, indicating a robust immune response from the CAR T cells.

Remarkably, this approach did not necessitate preconditioning. Usually, chemotherapy is given to create space for new CAR T cells by depleting existing immune cells, risking side effects such as infertility. “We were surprised that no chemotherapy was required,” says Ishihara. His team aspires to commence human clinical trials within the next two years.

“This is a promising avenue that warrants clinical testing,” stated Stephen Albelda from the University of Pennsylvania. He noted that numerous research groups are also exploring similar methods for tumor-targeted localization of interleukin-12, with encouraging results being reported.