Novel personalized immunotherapy showed promising results as a treatment option for cholangiocarcinoma (CCA), according to a study recently published in Cancer Communications.
“In this study, we enhanced the [chimeric antigen receptor (CAR)]-T cell antitumor function through a novel engineering strategy that combined the inhibitory effects of multiple checkpoints and immunosuppressive cytokine receptors,” the authors wrote.
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This experimental study used 4 different human cell lines, including the human CCA cell lines TFK-1 and HuCCT1, as well as peripheral blood mononuclear cells from healthy volunteers as the control group to investigate the effects of modifying the expression of specific genes. First, the researchers determined the expression pattern of the epidermal growth factor receptor (EGFR) and B7 homolog 3 protein (B7H3) antigens in tissue derived from patients with CCA.
Moreover, the authors developed CAR-T cells targeting the EGFR and B7H3 antigens and observed in vitro activity against tumor cells.
Importantly, CD8+ T cells in CCA tissue displayed high levels of programmed cell death protein 1 (PD-1), T-cell immunoglobulin and mucin domain-containing protein 3 (Tim-3), and T-cell immunoglobulin and ITIM domain (Tigit). Given these findings, the investigators knocked down the expression of all 3 surface proteins on CAR-T cells while also downregulating the expression of interleukin (IL)-10 and IL-6 receptors and transforming growth factor beta receptor.
The newly engineered cells, called PTG-scFV-CAR-T cells, exhibited antitumoral activity by killing neoplastic cells and inducing their apoptosis in an in vitro CCA organoid model.
Furthermore, the same cells were tested in vivo using a mouse model of CCA and showcased even better results, with greater inhibitory effects on tumor growth, leading to longer survival of the mice that received such treatment.
These results represent a potential novel treatment strategy for a neoplasm that currently lacks effective curative treatment, with the possibility of further personalizing the therapeutic approach for each patient with CCA.
“Either the combination of CAR-T cells with checkpoint antibodies or the down-regulation of intrinsic PD-1 in CAR-T cells enhances their antitumor properties,” the authors concluded.
Qiao Y, Chen J, Wang X, et al. Enhancement of CAR-T cell activity against cholangiocarcinoma by simultaneous knockdown of six inhibitory membrane proteins. Cancer Commun (Lond). Published online June 6, 2023. doi:10.1002/cac2.12452