Pros and Cons of Immunotherapy: CAR-T, NK and CAR-NK Cells II
Antitumor Effect of CAR-NK
- Blood tumors
In recent years, CAR-T has made major breakthroughs in the research of leukemia treatment. At the same time, people have also paid attention to the effects of NK cells on blood tumors such as leukemia, lymphoma and multiple bone marrow cancer. Compared with CD20 and CD19 receptor-modified NK-92, compared with NK-92 cells with ADCC function obtained by genetically expressing CD16, CAR-modified NK-92 cells have more significant clearance ability for chronic lymphocytic leukemia cells, indicating that CAR can mediate a stronger killing effect than ADCC in NK-92.
- Solid tumor
In addition to blood tumors, NK-92 cells have also achieved significant results in solid tumor research. Targeted killing of solid tumors can be achieved through potential tumor targets such as GD2, HER2, CD138 and CS1. ErbB2-CAR modified NK-92 cells significantly enhanced the killing effect on tumor cell lines such as HER2-positive breast cancer, ovarian cancer, and epithelial cancer, and could effectively slow tumor growth in mouse models. GD2 receptor modification enables NK-92 to target glioma cells and GD2-positive melanoma and breast cancer cells and exert cytolytic effect. The ligand of the NK cell surface activation receptor NKG2D is expressed in most malignant tumor cells. Therefore, the extracellular region of NKG2D on the surface of NK cells is directly bound to CD3ζ, and DAP10 is used as a second signal molecule to enhance the expression of NKG2D to a greater extent and amplify downstream activation signals. This design is used in acute lymphocytic leukemia and prostate cancer. And rhabdomyosarcoma and other malignant tumor cell lines have obvious killing effect.
Clinical transformation of CAR-NK
Although CAR-NK has made many advances in pre-clinical research, its progress in clinical translation is still relatively limited compared with CAR-T. A large number of clinical trials have begun to use CAR-T, and few clinical studies of CAR-NK have been approved for patients.
The results show that CAR-NK-based immunotherapy has obvious advantages over current CAR-T cell-based immunotherapy, because NK cells can be off-the-shelf (ready-to-use products) without the need to match with patients.
Scientists at the University of California, San Diego School of Medicine and the University of Minnesota have collaborated to discover that CAR-NK cells derived from iPSCs may have a clear advantage over T cells. In their research, scientists constructed a mouse model of ovarian cancer xenograft to detect CAR-NK cells derived from human iPSCs and compare their antitumor activity with other versions of NK cells and CAR-T cells . It was found that CAR-NK cells derived from human iPSCs showed similar anti-cancer activities as CAR-T cells, but with less toxic and side effects.
The results show that ovarian cancer is a good attempt. "Using NK cells may be safer," Kaufman said. He is working with scientists at San Diego-based Fate Therapeutics to advance clinical trials. In the future, they will continue to verify the feasibility of CAR-NK cells derived from iPSCs in solid tumors such as breast cancer, brain tumors, and blood cancers such as leukemia.
Reference
CRUZ,C.R.Y., MICKLETHWAITE,K.P., SAVOLDO,B.,et al. Infusion of donor-derived CD19-redirected virus-specific T cells for B-cell malignancies relapsed After allogeneic stem cell transplant: A phase 1 study[J]. Blood: The Journal of the American Society of Hematology,2013,17(17):2965-2973.
MORGAN E. WALLACE, MARK J. SMYTH. The role of natural killer cells in tumor control-effectors and regulators of adaptive immunity[J]. Springer Seminars in Immunopathology,2005,1(1):49-64.
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