SUMMARY:
Researchers at UCLA’s School of Dentistry have developed methods and protocols for culturing and priming various immune cells into a “supercharged” phenotype. The studied cell types include NK and iNKT cells, gamma delta T cells, and CD8+ T cells. When deployed in combination, these supercharged cells were found to eliminate both poorly and well-differentiated oral and pancreatic tumours and cancer stem cells, and thus are well suited for dealing with heterogenous tumor types.
BACKGROUND:
Biomedical research over the last two decades has highlighted the role of the immune system in stopping or slowing tumorigenesis while showcasing the importance of the immunological state of the tumor. This has made it possible to target tumors with immunotherapeutic approaches such as chimeric antigen receptor (CAR) T-cell therapy. More recent discoveries have made it clear that different immune cell populations such as natural killer cells (NK), or specific subsets of T-cell populations such as gamma delta T cells and supercharged CD8+ T cells can also be isolated from patients and redeployed as directed therapeutic intervention against various cancers. However, such approaches have suffered from a similar theme in their limitations to fully eliminate the tumor: the eventual development of resistance or inability to turn the tumors responsive. These obstacles are in part a result of the heterogeneous nature of cancer as well as the varying capacities of the different types of immune cells to preferentially target some cell types over others. These issues are further confounded by the isolation and culturing process which may reduce therapeutic capacity of the immune cells. For further maturation of immunotherapeutic approaches, new culturing and expansions strategies are needed alongside improved methods for managing the heterogeneous nature of tumors.
INNOVATION:
UCLA researchers from the laboratory of Dr. Anahid Jewett have previously discovered and established protocols for using osteoclasts to effectively expand and/or activate gamma delta T (gdT) cells, various types of T cells (e.g., CD8+ T cells, CD3 T cells), and/or invariant natural killer T (iNKT) cells. These coculturing protocols result in a “supercharged” phenotype where the expanded cells elicit an improved and robust response against the tumor. These supercharged immune cells were also found to preferentially target different aspects of the tumor. For example, supercharged NK cells are more adept at eliminating cancer stem cells, while other types preferentially target highly differentiated tumors. Finally, these supercharged phenotypes have been shown to target and reduce tumor size in pancreatic and oral cancer models. In instances where different supercharged types are combined, a greater response and reduction of the tumor burden has been observed.
POTENTIAL APPLICATIONS:
• Treatment of both oral and pancreatic tumours
• Targeting cancer-stem cells
• Treatment of immunologically cold tumours
ADVANTAGES:
• Combination treatment addresses the pitfalls of single cell-type immune therapies
• Suited for treatment of heterogenous tumours
• Supercharged cells better target autologous tumours
DEVELOPMENT-TO-DATE:
Protocols for priming and culturing of supercharged immune cells have been established. Analyses in in vitro models and in vivo humanized mice models show supercharged cells cooperate to eliminate cancer stem cells/poorly differentiated tumors and well differentiated tumors.
Related Papers (from the inventors only):
1. Kaur K, Cook J, Park S, Topchyan P, Kozlowska A, Ohanian N, Fang C, Nishimura I and Jewett A (2017). Novel strategy to expand super-charged NK cells with significant potential to lyse and differentiate cancer stem cells; Differences in NK expansion and function between healthy and cancer patients. Front. Immunol 7:9. doi:10.3389/fonc.2017.00009
2. Anna Kozlowska, Paytsar Topchyan, Kawaljit Kaur, Han-Ching Tseng, Antonia Teruel, Toru Hiraga, and Anahid Jewett, Differentiation by NK cells is a prerequisite for effective targeting of cancer stem cells/poorly differentiated tumors by chemopreventive and chemotherapeutic drugs; Journal of Cancer, 2017; 8(4):537-554. doi: 10.7150/jca.15989
3. Kaur, K., P. Topchyan, A. K. Kozlowska, N. Ohanian, J. Chiang, P. O. Maung, S.-H. Park, M.-W. Ko, C. Fang, I. Nishimura and A. Jewett (2018). "Super-charged NK cells inhibit growth and progression of stem-like/poorly differentiated oral tumors in vivo in humanized BLT mice; effect on tumor differentiation and response to chemotherapeutic drugs. Oncoimmunology. 2018 Feb 22;7(5):e1426518. doi: 10.1080/2162402X.2018.1426518. eCollection 2018
4. Kawaljit Kaur, Meng-Wei Ko, Nick Ohanian, Jessica cook, Anahid Jewett. Osteoclast-expanded super-charged NK cells preferentially select and expand CD8+ T cells. Scientific Reports 10, 20363 (2020). https://doi.org/10.1038/s41598-020-76702-1