Abstract
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.
Highlights
Immunotherapy especially immune checkpoint inhibitors (ICI) and Chimeric antigen receptor (CAR)-T therapy is emerging as one of the most promising approaches for relapse and refractory malignancies in the past decades [1]
Naive CD8+ T cells were infected with the retrovirus-mediated transduction, which led to the surface expression of carcinoembryonic antigen (CEA) CAR (Myc+) (Figure 1C) and exogenous expression of B-cell lymphoma-extra large (Bcl-xL) (32 kDa; Figure 1D)
CAR-T cell persistence has been associated with better clinical outcome in both patients with blood malignancies and solid tumors [33, 34]
Summary
Immunotherapy especially immune checkpoint inhibitors (ICI) and CAR-T therapy is emerging as one of the most promising approaches for relapse and refractory malignancies in the past decades [1]. Selecting favorable target antigens to avoid on-target off-tumor adverse effect; enhancing the ability of infused cells to accumulate in the high-density tumor lesion; and improvement of proliferation and/or persistence of the infused cells within the tumor mass [5]. Amongst these obstacles, the lack of proliferation and/or persistence may be responsible to a great extent for the poor effect of CAR-T therapy in solid tumors. Even for hematological malignancies with complete remission rate as high as to 90%, the patients remain at the risk of relapse because of the poor persistence of CAR-T cells in vivo. Effective strategies to circumventing these barriers should significantly improve current tumor immunotherapy, are urgently needed [6]
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