Researchers restore CAR T cells to act as ‘micro-pharmacies’ for cancer medicine

Cancer cells

Electron microscopic image of a single human lymphocyte. Credit: Dr. Triche National Cancer Institute

Immunotherapies called chimeric antigen receptors (CAR) T cells use genetically engineered versions of a patient’s own immune cells to fight cancer. These treatments have provided energy for cancer treatment, especially for people with certain types of blood cancer. Now, researchers at the Memorial Sloan Kettering Cancer Center’s Sloan Kettering Institute (SKI) have developed new CAR T cells that can do something their predecessors did not: Manufacture drugs.

Standard Edition CAR T cells are designed in the laboratory to recognize specific markers on cancer cells. When these CAR T cells are given back to a patient, they multiply and go on the attack, acting as a kind of “living substance”.

Despite their usefulness in the treatment of blood cancer, there are several limitations of current CAR T models. One is that CAR T cells can only kill cancer cells that contain the marker they are designed to recognize. But it is not uncommon for cancer cells to stop making this marker and thus “escape” from therapy.

Another problem is that CAR T cells can become “exhausted” – and even inhibited by the cancer cells themselves. Finally, existing CAR T cells only work well against blood cancers, which the CAR T cells can easily reach. Faced with dense solid tumors in the lung or breast, they are mostly powerless.

To overcome these obstacles, a team of SKI researchers has designed a completely new type of CAR T cell that acts as a “micropharmacy”: It can deliver a toxic drug load directly to a tumor and kill both tumor cells that contain the cancer marker as f as well as the cancer cells nearby that do not. What’s more, the engineered cells can produce the substance, even after they have become exhausted, and the substance is not suppressed by the cancer.

“We call them SEAKER cells,” says medical scientist David A. Scheinberg, president of the Molecular Pharmacology Program at SKI, which also heads the Center for Experimental Therapeutics. “SEAKER stands for Synthetic Enzyme-Armed KillER cells. These cells combine the targeting power of immune cells with the ability to locally generate a potent double-acting cancer drug.”

The anti-cancer molecule is one that the chairman of the SKI Chemical Biology Program Derek Tan — Dr. Scheinberg’s collaborator on the project – discovered earlier while developing antibiotics. The molecule, called AMS, is so powerful that it cannot be injected directly into an animal’s bloodstream. However, when produced locally at the site of a tumor, it is effective in safely killing cancer cells in mice. Researchers have not yet tested the technology in humans.

Details of the SEAKER platform, which researchers say are applicable to both cancer and other diseases, were published on December 30, 2021, in Chemical biology of nature.

A unique approach to drug delivery

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

“Human cells can not normally make this type of connection,” says Dr. Tan.

To find a solution, the team devised a smart approach. They linked the cancer drug to another chemical that “masks” its function. They then genetically engineered the T cells to make an enzyme that cuts the masking molecule from the substance.

“Unlike small-molecule drugs, human cells are very good at making enzymes, so CAR T cells are able to produce it efficiently,” adds Dr. Tan.

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 as a scissors and releases the active part of the prodrug at the site of the tumor.

The researchers tested their SEAKER cells on both cancer cells growing in a dish and in mouse models. In both cases, the SEAKER cells performed better than normal CAR T cells in killing the cancer cells.

The SKI team also showed that their SEAKER cells work with several different prodrugs and several different cleavage enzymes – which is why they refer to this technology as a “platform”.

A risky bet that paid off

The researchers emphasize the “high risk, high reward” nature of their research.

“It’s one of the wildest ideas I’ve ever worked on,” says Dr. Tan. “It’s very exciting that we made it work.”

Thanks to start-up funding from MSK’s Center for Experimental Therapeutics and Philanthropy, they were able to take a risk and eventually get the idea going. Later, the National Institutes of Health (NIH) provided additional funding.

Dr. Tan adds that this project is a good example of how the practice of non-cancer-related basic science at MSK can spawn new discoveries relevant to cancer.

Excludes cancer and other diseases

Now that researchers have shown that their SEAKER cells work in mice, there has been great interest in the approach. In fact, a company called CoImmune has already licensed the technology from MSK to develop the CAR T cell technology for human testing.

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

“The collaboration with CoImmune is exciting because we need a company to take on this to scale up and manufacture a standardized product,” adds Dr. Scheinberg.

Another part of the appeal of SEAKER technology is that it has more than one possible application.

“You could imagine it being used to produce drugs to fight other conditions, such as autoimmune diseases and infections,” says Dr. Scheinberg.

But for now, the focus of MSK researchers and CoImmunes will be on cancer. Dr. Scheinberg speculates that a clinical trial of cancer is about two to three years away.

CAR-T immunotherapy could be improved to kill solid tumors

More information:
TJ Gardner et al., Engineering CAR-T Cells to Activate Small Molecular Drugs in Situ, Chemical biology of nature (2021). DOI: 10.1038 / s41589-021-00932-1

Provided by Memorial Sloan Kettering Cancer Center

Citation: Researchers restore CAR T cells to serve as ‘micro-pharmacies’ for cancer drugs (2021, December 30) Retrieved December 31, 2021 from -micropharmacies. html

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