FRONT PAGES: UCLA Researchers Make Progress Toward An ‘off The Shelf’ Immune Cell Therapy Against Cancer

dWeb.News Article from Daniel Webster dWeb.News

Newswise — Immunotherapies harness the body’s natural defenses in order to fight disease and have revolutionized the treatment for deadly and aggressive cancers. These therapies, especially those that are based on immune cells, can be costly and time-consuming to create for each patient.

Now in a paper published by Cell Reports Medicine, UCLA researchers have made a significant step in developing an “off the shelf” cancer immunotherapy that uses rare, powerful immune cells. These cells can be stored for long periods of time and could be used safely to treat many patients with different cancers.

“We want to reach as many patients as possible, so we need cell therapies that are mass-produced, frozen, and shipped to all countries,” Lili Yang, who is a senior author of the study and a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, at UCLA , said. This will allow us to have the right doses for our patients .”

Researchers developed a new way to produce large quantities of these iNKT cell using blood-forming stem cells. These cells can self-replicate and make all types of immune cells and blood. The stem cells were taken from eight donors and four cord blood samples.

“Our findings suggest that one cord blood donation could produce up to 5,000 doses of the therapy and one peripheral blood donation could produce up to 300,000 doses,” said Yang, who is also an associate professor of microbiology, immunology and molecular genetics and a member of the UCLA Jonsson Comprehensive Cancer Center. “At this yield, the cost of producing immune cell products could be dramatically reduced.”

The researchers first used genetic engineering to program the blood-forming stem cells to make them more likely to develop into iNKT cells. These genetically engineered stem cell were then placed in artificial thymic orboids that mimic the environment in which T cells mature naturally in the body. After eight weeks in the organoids, each stem cell produced, on average, 100,000 iNKT cells.

Yang, her collaborators, then tested the cells. They were called hematopoietic cell-engineered INKT cells or HSC-iNKT. The cells were compared with immune cells known as natural killer cells or NK cells to determine their ability to fight cancer. The researchers discovered that HSC-iNKT cells killed multiple types of human cancer cells in a laboratory dish. They were more effective than NK cells at killing them.

Even more important, HSC-iNKT cells retained their tumor-killing effectiveness after being frozen and then thawed. This is a critical requirement for widespread distribution.

Next, the researchers equipped HSC-iNKT cells using a chimeric antibody receptor (or CAR) which is a specialized molecule that allows immune cells to recognize and destroy a particular type of cancer. They added to HSC-iNKT cells the CAR that targets multiple myeloma cell protein and tested their ability to fight multiple myeloma cancers from mice that were transplanted.

These CAR-equipped HSC–iNKT cells eradicated multiple myeloma tumours. Mice that received this treatment were free from tumors and had no signs of graft-versus host disease.

The researchers are currently working to improve their manufacturing processes by switching to a feeder-free method that eliminates the requirement for supporting cells, such as those found in the thymic oroids to aid blood stem cells in making iNKT cells. Yang hopes that this breakthrough will allow mass production of the therapy, and ultimately its commercial and clinical development.

The paper’s coauthors are Yan-Ruide Li (Charlie), and Yang (Alice), both UCLA doctoral students. UCLA professors Dr. Sarah Larson and Dr. Joshua Sasine, Matteo Pellegrini and Dr. Owen Witte are additional authors.

The genetic engineering of blood-forming stem cell cells by the researchers was done using methods devised by Dr. Donald Kohn. Dr. Antoni Ribas also developed artificial thymic organoids. Gay Crooks and Dr. Chris Seet, all from the UCLA Broad Stem Cell Research Center, are also listed.

The methods and products described in this research are covered by patent applications that were filed by UCLA Technology Development Group for the Regents of California. Seet, Yang, Yu Jeong Kim and Jiaji Yu were listed as co-inventors. This treatment strategy was only used in preclinical trials. It has not been approved for human use by the U.S. Food and Drug Administration.

Funding for this study was provided by The National Institutes of Health and the California Institute for Regenerative Medicine.

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