Adjuvant for immunotherapy

One of the promising cancer treatment strategies is to stimulate the body's own immune system to fight cancer cells. But some tumors are protected and suppress the immune system, so immunotherapy does not work in all patients.

Researchers from the Massachusetts Institute of Technology have found a way to increase the effectiveness of one type of cancer immunotherapy. In mouse models of cancer, they showed that if treatment with checkpoint inhibitors is enhanced with new nanoparticles that additionally stimulate the immune system. The effect is more powerful than with monotherapy with checkpoint inhibitors. The researchers claim that this approach will help make cancer immunotherapy useful to a larger percentage of patients.

A team led by Colin Buss has developed a way to package and deliver small fragments of DNA that trigger an immune response to tumor proteins. This synergistic effect makes checkpoint inhibitors more effective. In studies on mice, the combined treatment stopped the growth of the target tumor, and in some cases also stopped the growth of tumors in other parts of the body.

Without brakes

The human immune system is able to recognize and destroy abnormal cells. However, many tumors secrete molecules that suppress the immune system in its environment.

The idea of checkpoint inhibitors is that they can remove this "brake" from the immune system and restore the ability of T cells to attack tumors. Some of these inhibitors (CTLA-4, PD-1, PD-L1) are already approved for the treatment of various types of cancer. They work by disabling proteins that prevent the activation of T cells.

In some patients, checkpoint inhibitors work quite well, leading to the cure of up to 15-20 percent of patients. A lot of work needs to be done to make it possible to use this approach for more patients.

Some studies have shown that combining checkpoint inhibitors with radiation therapy can make them more effective. Another approach that the researchers have tried is to combine them with immunostimulating drugs. One of these drugs are oligonucleotides – specific DNA or RNA sequences that the immune system recognizes as foreign. But clinical trials of immunostimulating drugs have not been successful, and one possible reason is that the drugs do not reach the target. Buss's group decided to find a way to achieve more accurate delivery of these immunostimulating drugs, allowing them to accumulate in tumors.

To do this, they packed oligonucleotides into tumor-penetrating peptides that they had previously developed to deliver RNA that suppresses cancer genes. These peptides can interact with proteins on the surface of cancer cells, and with their help they specifically target tumors. Peptides have positively charged segments in their composition that help to penetrate the cell membranes of cancer cells.

Nanoparticles enhancing cancer immunotherapy (transmission electron microscopy). Source: MIT News.

The oligonucleotides used in this study contained a specific DNA sequence that is often found in bacteria, but not in human cells, so that the human immune system can recognize it and respond. These oligonucleotides specifically activated the so-called toll-like receptors on the surface of immune cells, whose function is to detect microbial agents.

Synergistic effect

After creating the nanoparticles, the researchers tested them on several different models of cancer in mice. They separately tested oligonucleotide nanoparticles and checkpoint inhibitors, and then two treatment options simultaneously. The combination of both methods gave a noticeably better result.

The researchers also wondered if it was possible to stimulate the immune system to target tumors that had already metastasized throughout the body. To test this, they implanted two tumors in mice, one on each side of the body. Mice received systemic treatment with a checkpoint inhibitor, and nanoparticles were treated locally, only in one tumor. The researchers found that the T cells activated by the combined treatment were able to attack both tumors.

Currently, the researchers plan to test the safety of nanoparticles in order to use them in the future for the treatment of patients whose tumors do not respond to monotherapy with checkpoint inhibitors.

Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on MIT News: A boost for cancer immunotherapy.