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Preclinical development of tumor-infiltrating lymphocyte therapy for ovarian cancer
Journal for ImmunoTherapy of Cancer volume 3, Article number: P48 (2015)
Immunotherapy has become an effective cancer therapy, particularly in the case of checkpoint blockade and adoptive T cell therapy (ACT). ACT exploits the presence of tumor-infiltrating lymphocytes (TIL) by exponentially expanding their numbers ex vivo and re-infusing them into the patient in an autologous setting. With the effectiveness of TIL therapy already well established in multiple Phase II studies in melanoma, there is a push to translate it to other malignancies such as ovarian cancer (OvCa) .
The presence of TIL is correlated with greatly increased survival in OvCa [2, 3] suggesting that TIL effectively control the disease and provide a rationale to test TIL therapy in this setting. To assess the feasibility, we characterized the immune component of OvCa, explored the ability to grow & expand TIL from tumor fragments, and tested their functionality.
Extensive flow cytometry analysis detected a robust, activated T cell infiltrate that can be grown from OvCa samples obtained pre- and post-chemotherapy. The addition of an agonistic anti-41BB antibody to the cultures preferentially increased CD8+ TIL outgrowth as well as favored the expansion of NK cells. Importantly, success rate of TIL growth was increased from 40% to 90% for cultures grown without and with anti-41BB respectively. It was established next that the CD3+ TIL initially grown with anti-41BB could be rapidly expanded at least 1000 fold over two weeks. Finally, the rapidly expanded T cells exhibited anti-tumor capabilities in the context of re-directed killing assays.
In conclusion, further flow cytometry analysis to identify other agonistic and inhibitory targets is needed along with additional in vitro and in vivo experiments. However, the initial data suggest that TIL therapy for OvCa could be a viable therapeutic option in the future.
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Milne K, Kobel M, Kalloger SE, Barnes RO, Gao D, Gilks CV, et al: Systematic analysis of immune infiltrates in high-grade serious ovarian cancers reveals CD20, FoxP3, and TIA-1 as positive prognostic factors. PLoS One. 2009, 4: e6412-
Nielsen JS, Sahota RA, Milne K, Kost SE, Nesslinger NJ, Watson PH, et al: CD20+ tumor-infiltrating lymphocytes have an atypical CD27-memory phenotype and together with CD8+ T cells promote favorable prognosis in ovarian cancer. Clin Cancer Res. 2012, 18 (12): 3281-3292.
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Sakellariou-Thompson, D., Haymaker, C., Forget, M. et al. Preclinical development of tumor-infiltrating lymphocyte therapy for ovarian cancer. j. immunotherapy cancer 3, P48 (2015). https://doi.org/10.1186/2051-1426-3-S2-P48
- Ovarian Cancer
- Flow Cytometry Analysis
- Extensive Flow
- Preclinical Development