An engineered HSC–iNKT cell (blue) attacking a human tumor cell. Image: Yang Lab/UCLA
UCLA RESEARCHERS ARE REPORTING A CRITICAL STEP FORWARD in the development of an “off-the-shelf ” cancer immunotherapy using rare but powerful immune cells that could potentially be produced in large quantities, stored for extended periods and safely used to treat a wide range of patients with various cancers.
Immunotherapies, which harness the body’s natural defenses to combat disease, have revolutionized the treatment of aggressive and deadly cancers. But often, these therapies must be tailored to the individual patient, costing valuable time and pushing their price into the hundreds of thousands of dollars. “In order to reach the most patients, we want cell therapies that can be mass-produced, frozen and shipped to hospitals around the world,” says Lili Yang, PhD, a member of the Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research at UCLA. For the study, Dr. Yang and her colleagues focused on invariant natural killer T cells, or iNKT cells. These are unique not only for their power and efficacy but also because they don’t carry the risk of graft-versus-host disease, which occurs when transplanted cells attack a recipient’s body, and which is the reason most cell-based immunotherapies must be created on a patient-specific basis.
The researchers developed a new method for producing large numbers of these iNKT cel ls by genetically engineering blood-forming stem cells — which can self-replicate and produce all kinds of blood and immune cells — to make them more likely to develop into iNKT cells. Next, these stem cells were placed into artificial thymic organoids, which mimic the environment of the thymus, a specialized organ in which T cells naturally mature in the body. After eight weeks in the organoids, each stem cell produced, on average, 100,000 iNKT cells.
Dr. Yang and he r collaborators tested the resulting cells, called hematopoietic stem cellengineered iNKT cells, or HSC–iNKT cells, by comparing their cancer fighting abilities with those of immune cells called natural killer cells, or NK cells. In a lab dish, the HSC–iNKT cells were significantly better at killing multiple types of human tumor cells — including leukemia, melanoma, lung cancer, prostate cancer and multiple myeloma cells — than the NK cells. More importantly, the HSC– iNKT cells sustained their tumor-killing efficacy after being frozen and thawed, an essential requirement for widespread distribution of an off-the-shelf cell therapy.
The researchers next equipped the HSC–iNKT cells with a chimeric antigen receptor (CAR) that targets a protein found on multiple myeloma cells, and then tested the cells’ ability to fight human multiple myeloma tumors that had been transplanted into mice. These CAR-equipped HSC– iNKT cells eliminated the multiple myeloma tumors, and the mice that underwent this treatment remained tumor-free and showed no signs of graft-versus-host disease throughout their lives. The researchers are now working to move to a system that eliminates the need for supportive cells — such as those used in the thymic organoids — in producing iNKT cells. Dr. Yang says she hopes this will better enable mass-production of the therapy and, ultimately, its clinical and commercial development.
—Tiare Dunlap
“Development of Allogeneic HSC-engineered iNKT Cells for Off-the-Shelf Cancer Immunotherpay,” Cell Reports Medicine, November 16, 2021.
