Genetically Engineered CAR T Cells Serve as ‘Micropharmacies’ for Cancer Drugs

Newly-developed chimeric antigen receptor (CAR) T cells have been developed to produce anti-cancer drugs that are not suppressed by the cancer even after they have become exhausted, according to researchers at Memorial Sloan Kettering Cancer Center.

CAR T cells use genetically engineered versions of patients’ own immune cells to fight cancer. The emergence of these treatments has been a major development for patients, especially those with certain types of blood cancers.

Standard-issue CAR T cells are extracted from the patient and then designed in a lab to recognize specific markers on cancer cells. When these CAR T cells are returned to the patient, they proliferate and attack the cancer cells, acting as a sort of “living drug,” according to the researchers.

Despite their usefulness in blood cancers, current CAR T models have several significant limitations. One is that the CAR T cells can only kill cancer cells that contain the marker they are designed to recognize, so it is common for cancer cells to stop making this marker and to thus escape from the therapy.

Furthermore, CAR T cells can become exhausted and even inhibited by the cancer cells themselves, according to the researchers. Lastly, existing CAR T cells work well only against blood cancers that the CAR T cells can easily reach and they are mostly powerless against dense solid tumors in the lung or breast.

To overcome these problems, a team of researchers designed a novel type of CAR T cells that acts as a “micropharmacy,” according to the press release. The CAR T cells can deliver a toxic drug payload directly to a tumor, killing tumor cells that contain the cancer marker and nearby cancer cells that do not. Furthermore, the engineered cells can produce the drug even after they become exhausted, and the drug is not suppressed by the cancer.

“We call them SEAKER cells,” said David A. Scheinberg, MD, PhD, director of the Center for Experimental Therapeutics, in the press release. “SEAKER stands for Synthetic Enzyme-Armed KillER cells. These cells combine the target-seeking power of immune cells with the ability to locally generate a potent anticancer drug for double effect.”

The idea of using CAR T cells to deliver additional therapeutic agents is not entirely new. Several earlier research groups have found that it is possible to get CAR T cells to make immune proteins, such as antibodies and cytokines, but getting CAR T cells to produce a small-molecule cancer drug is more difficult.

“Human cells cannot normally make this type of compound,” said Sloan Kettering Institute Chemical Biology Program Chair Derek Tan, PhD, in the press release.

To find a way around this hurdle, the research team linked the cancer drug to another chemical that disguises its function. Then, they genetically engineered the T cells to make an enzyme that cuts the masking molecule from the drug. Unlike small-molecule drugs, Tan noted that human cells are very effective at making enzymes, so CAR T cells can produce it effectively.

When the inactive version of the drug, called a prodrug, is injected into the bloodstream, it circulates through the body. The enzyme produced by the CAR T cells acts like a scissor, releasing the active part of the prodrug at the site of the tumor. The team tested their SEAKER cells on both in vitro cancer cells and in mouse models, both of which performed better than regular CAR T cells.

The cancer-fighting molecule used in the SEAKER cells was previously discovered while developing antibiotics. The molecule, called AMS, is so powerful that it cannot be injected directly into an animal’s bloodstream, according to the press release. However, when it is produced locally just at the tumor site, it is effective at safely killing cancer cells in mice. The researchers have not yet tested the SEAKER cells in humans.

Now that the researchers have shown that the SEAKER cells work in mice, the press release said there has been a lot of interest in the approach. A company called CoImmune has already licensed the technology to develop the SEAKER cells for human trials.

“There is an opportunity to better understand the limitations of CAR T cells and specifically engineer new treatment options that have the potential to address challenges with eliminating tumor masses and toxicity,” said Charles Nicolette, PhD, CEO of CoImmune, in the press release. “This exciting collaboration positions us to evaluate this completely novel approach that may provide a new treatment option for patients with solid tumors.”

REFERENCE

Sloan Kettering Institute Scientists Retool CAR T Cells to Serve as ‘Micropharmacies’ for Cancer Drugs. News release. Sloan Kettering Institute; December 30, 2021. Accessed January 28, 2022. https://www.mskcc.org/news/sloan-kettering-institute-scientists-retool-car-cells-serve-micropharmacies-cancer-drugs?_subsite=research-ski