Journal
FRONTIERS IN ONCOLOGY
Volume 10, Issue -, Pages -Publisher
FRONTIERS MEDIA SA
DOI: 10.3389/fonc.2020.574860
Keywords
chimeric antigen receptor; T cells; persistence; solid tumor; immunotherapy
Categories
Funding
- National Institutes of Health [R01AI121180, R21AI128325, R01CA221867]
- American Diabetes Association [1-16-IBS-281]
- National Natural Science Foundation of China [81573751]
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The study developed a retroviral CAR construct with a second-generation carcinoembryonic antigen (CEA)-targeting CAR and the Bcl-xL gene, which significantly enhanced CAR-T cell accumulation in tumor tissues, suppressed tumor growth, and increased overall survival in a murine colorectal cancer model. This novel CAR-T platform has the potential to boost CAR-T immunotherapy for solid tumors by increasing cell persistence through exogenous expression of persistent genes.
Chimeric antigen receptor (CAR) T (CAR-T) cell transfer has made great success in hematological malignancies, but only shown a limited effect on solid tumors. One of the major hurdles is the poor persistence of infused cells derived from ex vivo activation/expansion and repeated antigen encounter after re-infusion. Bcl-xL has been demonstrated to play an important role on normal T cell survival and function as well as genetically engineered cells. In the current study, we developed a retroviral CAR construct containing a second-generation carcinoembryonic antigen (CEA)-targeting CAR with the Bcl-xL gene and tested the anti-CEA CAR-T cell immunotherapy for colorectal cancer. In vitro, the anti-CEA CAR-T cells destroyed CEA-expressing tumor cells and sustained survival. In vivo, adoptive cell transfer of anti-CEA CAR-T cells significantly enhanced the ability of the CAR-T cells to accumulate in tumor tissues, suppress tumor growth and increase the overall survival rate of tumor-bearing mice in a murine model of colorectal cancer. These results demonstrate a novel CAR-T platform that has the ability to increase the persistence of CAR-T cells in solid tumors through exogenous expression of persistent genes. The data provide a potentially novel approach to augment CAR-T immunotherapy for solid tumors.
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