Arming T Cells with IL-24 Improves the Ability to Destroy Cancerous Cells

Altering T cells of the adaptive immune system to enable recognition of cancerous cells is a mainstream area of research these days. The approach of adding chimeric antigen receptors to T cells, tailored to a cancer, is well established for blood cancers, but still challenging for solid tumors, characterized a wide variety of cancerous cells and signatures. Researchers here show that genetic modification of T cells to produce IL-24 allows these immune cells to effectively destroy cancerous cells that lack recognizable surface features, so long as they are close to cancerous cells that can be recognized. Further, the process of cancer cell destruction via IL-24 leads to the ability of the immune system to later recognize those cells as cancerous, suppressing the possibility of recurrence of the cancer.

A protein called IL-24 attacks a variety of cancers in several different ways. Researchers now deliver the gene coding for IL-24, which is called MDA-7, to solid tumors using T cells. This isn't the first time T cells have been engineered for cancer immunotherapy. Chimeric antigen receptor T (CAR-T) cell therapy - which is designed to destroy cancer cells expressing specific surface molecules - has shown tremendous success for treating advanced cancers of the blood and lymphatic systems. But CAR-T has made limited progress on solid tumors, such as prostate cancer or melanoma, because the cells that make up those tumors aren't all the same, which blocks the engineered T cells from recognizing and attacking. Researchers armed T cells with MDA-7/IL-24 to target cancer more broadly.

At the sub-cellular level, MDA-7/IL-24 binds to receptors on the surface of cells and instructs them to make and release more copies of the MDA-7/IL-24 protein. If the cell is normal, the protein is simply secreted and no damage occurs. But if the cell is cancerous, MDA-7/IL-24 causes oxidative stress damage and ultimately cell death, not only within the primary tumor but also among its distant metastases - the cause of death in 90% of patients. As a result of this process, the immune system generates memory T cells that can theoretically kill the tumor if it ever comes back. At the whole tumor level, IL-24 also blocks blood vessel formation, starving tumors of the nutrients so badly needed to sustain their unchecked growth.

In mice with prostate cancer, melanoma, or other cancer metastases, MDA-7/IL-24-expressing T cells slowed or stopped cancer progression better than unmodified T cells. The researchers also discovered that arming T cells with MDA-7/IL-24 allowed them to survive better and multiply in the tumor microenvironment - the space right around the cancerous mass. In the clinic, this approach would involve extracting the patient's own T cells from tumor samples, genetically engineering them to express MDA-7/IL-24, growing millions of copies of the cells in the lab and finally transplanting them back into the patient. CAR-T cells could also be engineered to express MDA-7/IL-24.



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Posted by: Josep at May 10th, 2021 10:04 AM

If the trained T cells can prevent metastases the harder half of the job is already done. The tumor will be effectively benign and then can be reduced by other means (micro surgery, injecting site-specific poison/chemo/radio.

Posted by: Cuberat at May 10th, 2021 5:04 PM
Scientists find mechanism that eliminates senescent cells
by University of California, San Francisco

Credit: CC0 Public Domain
Scientists at UC San Francisco are learning how immune cells naturally clear the body of defunct-or senescent-cells that contribute to aging and many chronic diseases. Understanding this process may open new ways of treating age-related chronic diseases with immunotherapy.

In a healthy state, these immune cells-known as invariant Natural Killer T (iNKT) cells-function as a surveillance system, eliminating cells the body senses as foreign, including senescent cells, which have irreparable DNA damage. But the iNKT cells become less active with age and other factors like obesity that contribute to chronic disease.

Finding ways to stimulate this natural surveillance system offers an alternative to senolytic therapies, which to date have been the primary approach to removing senescent cells. It could be a boon to a field that has struggled with how to systemically administer these senolytics without serious side effects.

The iNKT cells have two attributes that make them an especially appealing drug target. First, they all have the same receptor, which does not appear on any other cell in the body, so they can be primed without also activating other types of immune cells. Second, they operate within a natural negative feedback loop that returns them to a dormant state after a period of activity.

"Using iNKT-targeted therapy can piggyback on their exquisite, built-in specificity," said Anil Bhushan, Ph.D., a professor of medicine at UCSF in the Diabetes Center and senior author of the paper, which appears May 10, 2021, in Med.

The scientific team found they could remove senescent cells by using lipid antigens to activate iNKT cells. When they treated mice with diet-induced obesity, their blood glucose levels improved, while mice with lung fibrosis had fewer damaged cells, and they also lived longer.

Mallar Bhattacharya, MD, associate professor of medicine at UCSF who treats patients with lung disease and is an author of the paper, said the results presented for iNKT cells in a mouse model of lung fibrosis offer hope for a potentially fatal disease that often leads to lung transplants.

"I think this is a potential immune therapy for senescence and fibrosis," Bhattacharya said. "It's a fairly well tolerated therapy, and we just have to get around dosing and trials."

A diabetes researcher, Bhushan first started paying attention to iNKT cells when a previous study identified a link between iNKT cells and senescent pancreatic beta cells. Because senescent cells tend to accumulate in many tissues and correlate with disease, he surmised that activating iNKT cells could be used to treat a wide variety of diseases.

Posted by: Robert Read at May 11th, 2021 5:02 AM

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