UC San Diego
Development of conditionally reprogrammed cells (CRCs) as an in vitro model for T-cell based cancer immunotherapy
- Author(s): Chen, Claire
- Advisor(s): Schoenberger, Stephen P
- et al.
Adoptive T-Cell Therapy (ACT) is a novel cancer therapy in which tumor-specific T-cells are obtained from patients, expanded in the laboratory, and then infused back into the patient to eradicate the cancerous cells. While conventional treatments for cancer such as surgery, radiation, and chemotherapy have been used to successfully eradicate tumors, they work by using non-specific methods to eliminate cancer cells, which in turn can also affect normal, healthy cells. Through Adoptive T-cell Therapy, we are able to take advantage of the natural ability of T-cells to recognize cancer cells and infuse them back into the patient to specifically target malignant tumors and avoid off-tumor toxicities. ACT has shown a lot of promise as a personal cancer treatment not only due to its ability to specifically target cancer, but also because ACT has been seen to produce deep, enduring responses especially in melanoma patients. Some current ways to increase efficacy in ACT treatment including lymphodepleting the patient prior by irradiation and/or using a chemotherapy drugs. While these methods have shown to enhance ACT outcomes, they can also result in serious side effects like fevers or infections that can be life-threatening for the patient. As a result, there is still a need to further study effective strategies that can improve the efficiency of ACT, and thus decrease complications for the patient.
To develop an in vitro model that that would allow researchers to better investigate ACT, we looked into the conditionally reprogrammed cell (CRC) methodology, which is an innovative protocol that allows for the generation of primary epithelial cancer cells in 7 days at a high success rate. To explore whether CRCs can be an immunological model for ACT, we generated conditionally reprogrammed cells from Head and Neck Squamous Cell Carcinoma tumors that express the same cancer mutations as the patient’s and presumably allow natural processing and presentation of antigen by MHC-I. Through this model, we were able to show CRCs can be recognized and killed by tumor-specific cytotoxic T-cells. In addition, when compared with cisplatin, a chemotherapy drug, cytotoxic T-cells were able to induce faster eradication of the cancer cells. We herein demonstrate that CRC models retain their original tumor phenotype by staining of cancer stem cell markers, CD44, EGFR, EpCam, BMI1, ALDH1 and have the ability to be used as an immunological surrogate for primary tumor in T-cell based cancer immunotherapies.