When Lili Yang was studying for her PhD she approached her mentor, the Nobel Laureate Dr. David Baltimore, and told him she was thinking about writing her thesis on a combination of gene therapy, immunotherapy and stem cell therapy. She says he looked at her and told her that all three of those approaches had a bad reputation because of so many past failures. He asked her, “Are you sure?” She was.
Fast forward 20 years and Dr. Yang and her team at UCLA have developed stem cell-engineered invariant Natural Killer T (iNKT) cells, a kind of specialized immune system cell, that has the ability to attack and kill a broad range of cancerous cells, while leaving the body’s healthy tissues unharmed.
Thanks to several CIRM grants, Dr. Yang has developed a platform that can use healthy donor blood stem cells to produce clinical scalable “off-the-shelf” iNKT cells. That has led to the creation of Appia Bio, a start-up company, and talks with the FDA about testing a series of iNKT cell products in clinical trials.
Besides developing cell products targeting the more established blood cancer disease indications, Dr. Yang is most excited about using the same platform to generate off-the-shelf iNKT cell products that could target solid tumor cancers that comprise over 90% of the total cancer cases, such as breast, ovarian, prostate, lung, liver, and colon cancers.
“I have this dream that cell therapy can become off-the-shelf, and how this would really help all cancer patients in need. The current cancer cell therapy requires treating patients one-by-one, resulting in a steep price that is hard to afford ($300,000-$500,000 per patient per treatment) and a complex therapy delivery logistics that is challenging to fulfill (coordination of hospitalization, blood collection, cell manufacturing and infusion for each patient). Not everyone lives near a hospital capable of handling such a personalized therapy or can afford such a steep price. If we can make this therapy with centralized manufacturing, pre-quality controlled and ready for wide use then we don’t need to worry about the gender or age or location of the patient. For off-the-shelf therapy, price is also expected to drop down significantly- this will eventually be ready for everyone everywhere.”
The Stem Cellar 
Invariant NKT (iNKT) cells are a specialized T cells population that recognizes lipid antigens that are presented by cell-surface molecule known CD-1d. iNKT cells are a subset of T lymphocytes that share surface markers and functional characteristic of T lymphocytes and natural killer cells. They recognize both foreign lipid antigens and self lipid antigens. iNKT cells become activated during a variety of infection, inflammatory conditions and rapidly producing large amounts of immunomodulatory cytokines. In addition, they can influence the activation state and functional properties of multiple other cell types in the immune system and that modulate immune responses against infectious agents, autoantigens, tumors, tissue grafts and antigen. Following stimulation, iNKT cells lead to downstream activation of both innate and adaptive immune cells in the tumor microenvironment. However, NK and iNKT cells have distinct distribution, phenotype profile in tumor sites, other peripheral organs and during the course of tumors development and progression. In the early stage of tumor development, both NK and iNKT cells exhibit effector properties. But the later of tumor stage, both have impaired cytotoxic capacities and dysfunctional status. NK cells become senescent cells while iNKT cells are exhausted in the advanced cancers. Further observation revealed that senescent NK cells have heightened glucose and lipid metabolism, but exhausted iNKT cells display imbalanced metabolism in tumor microenvironment of both breast and melanoma tumor models.
To note that, iNKT cells like other immune cells require further modification to enhance the antitumor capacity of iNKT. Another finding reported that expression of CD-1d antigens are mainly observed in myelomonocytic and B cell lineages origin, but very few CD-1d expression are found in solid tumors. This is supported by evidence that low expression of CD-1d antigens in tumor cells are correlated with low antitumor immunity of iNKT cells. If iNKT cells are being used as a solely agent for cancer therapy, more attention are required to focus on modification to improve the non-restricted MHC cytolytic of iNKT on cancer treatment.
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