As a PhD student, Lili Yang told her mentor, Nobel Laureate Dr. David Baltimore, that she wanted to combine gene therapy, immunotherapy, and stem cell therapy in her thesis. He warned her that all three fields had a poor reputation because of past failures. She said, “Are you sure?” She was.
Twenty years later, Dr. Yang and her UCLA team have developed stem‑cell‑engineered invariant Natural Killer T-cells (iNKT) that can attack a broad range of cancer cells while sparing healthy tissue.
With several CIRM grants, she built a platform that uses healthy donor blood stem cells to produce scalable, off‑the‑shelf iNKT cells. This work led to the creation of Appia Bio and discussions with the FDA about clinical testing.
In addition to targeting blood cancers, Dr. Yang is excited about using the same platform to generate off‑the‑shelf iNKT products for solid tumors, which make up more than 90 percent of cancer cases, including breast, ovarian, prostate, lung, liver, and colon cancers.
“I dream of making cell therapy off‑the‑shelf so it can help all cancer patients,” she says. “Current therapies must be made one patient at a time, at enormous cost and with complex logistics. Not everyone can travel to a hospital that offers such personalized care. Centralized, pre‑qualified manufacturing would make these therapies widely accessible. Costs would drop significantly. This could eventually be available to everyone, everywhere.”
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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