Science sub-journal: New co-stimulation signals enable CAR-T to demonstrate the potential for treating solid tumors

CAR-T therapy shows great strength in malignant blood tumors, and there are still many obstacles to the treatment of solid tumors.
The main reason lies in the difficulties of cell therapy of solid tumors, such as the heterogeneity of different types of solid tumors, the lack of unique tumor-related antigens as CAR-T target, T-cells can not effectively return to the tumor site, CAR-T cell sustainability is not enough, and complex microenvironents in tumors have an immune inhibitory effect.
, T-cell activity requires at least two signals, in addition to the first signal T-cell recognition of MHC-peptide compounds, the identification process of various signal stimuli is also necessary.
to the challenge of CAR-T cells in treating solid tumors, scientists have enhanced the persistence and anti-tumor activity of CAR-T cells by introducing new costulation domains, cytokine genes, and cytokine subjects into T-cells.
recently, a team of associate professors at Shanghai Jiaobi University, Yang Zhaoming, published a research paper in the journal Scienceal Medicine that ox40 co-stimulation signals can enhance CAR-T's anti-tumor activity.
Most co-stimulation signals are currently transducted with T-cell receptor signals during T-cell activity, but in this study, researchers designed a co-stimulation signal independent of T-cell receptors, which can be individually active to stimulate T-cells.
researchers screened 12 costulations, including ICOS, CD27, CD40L, CD30, and found that OX40 had the most significant effect on CAR-T amplification.
ox40 is one of the important types of T-cell costulation signals that are part of the tumor necrotic necrotic group (TNF) super family.
ox40 ligation OX40L (also known as CD252) combines the form of a trimer with the OX40 protein of three molecules to form a hexamer complex, thus activating signal path paths such as downstream NF-B, PI3K, and AKT.
the continuous activation of these downstream signals can stimulate the production of cytokines, prolong the survival time of T cells, inhibit the differentiation and activity of regulatory T-cells (Treg), and enhance the lethality of effect T-cells.
experiment, the researchers also found that OX40 reduced apoptosis of CAR-T cells by increasing gene expression coding members of the Bcl-2 family, and enhanced cell proliferation by increasing the activity of the NF-B, MAPK, and PI3K-AKT signaling path paths.
addition, the OX40 signal not only enhances the cytotoxicity of CAR-T cells, but also reduces the signs of failure, thus maintaining the function of CAR-T cells in immunosuppressive tumor micro-environments.
in vivo trials, OX40 costulation signal significantly enhances the anti-tumor activity of CAR-T cells, and has significant inhibitory effect on metastases, indicating that OX40 costration signal is expected to be used in the treatment of solid tumors.
based on the method of this experiment, the self-20BBZ-OX40 CAR-T therapy has entered the phase 1 clinical trial stage, which is currently showing good tolerance and efficacy in patients with B-cell lymphoma.
recent years, scientists have made considerable efforts to develop new ways to overcome solid tumor barriers and use optimization strategies for CAR-T therapies for these specific adaptations.
look forward to demonstrating the true ability of CAR-T to treat solid tumors as more and more technologies and clinical breakthroughs are made.
resources: . . . Huihui Zhang et al., A chimeric antigen receptor with antigen-independent OX40 signaling mediates potent antitumor activity. (2021) Science Translational Medicine. DOI: 10.1126/scitranslmed.aba7308.