Chimeric antigen receptor (CAR) expressing T cells (CAR-T therapy) is one of the major breakthroughs in the field of cancer treatment in recent years, and has achieved excellent results in the treatment of blood cancer. CAR is like a “GPS navigation system” for T cells, so that T cells can quickly locate tumor cells that are good at camouflage, so as to find and kill them. So far, two CAR-T therapies targeting CD19 have been successfully launched in the world for the treatment of B-cell malignancies.
CAR-T therapy has shown great strength in the treatment of hematological malignancies, but there are still many obstacles in the treatment of solid tumors. The main reason is that there are many difficulties in the cell therapy of solid tumors, such as the heterogeneity of different types of solid tumors, the lack of unique tumor-associated antigens as CAR-T targets, the inability of T cells to effectively homing to the tumor site, the insufficient persistence of CAR-T cells and the immunosuppressive effect of the complex microenvironment in tumors.
Generally, T cell activation requires at least two signals. In addition to the first signal, T cells recognize MHC peptide compounds, and various signal stimuli are also necessary for the process of recognition. To solve the problem of CAR-T cells in the treatment of solid tumors, scientists introduce new co-stimulatory domains, cytokine genes, and cytokine receptors into T cells to enhance the persistence and anti-tumor activity of CAR-T cells. Recently, Associate Professor Yang Xuanming’s team of Shanghai Jiaotong University published a research article in the journal Science Translational Medicine that OX40 co-stimulatory signal can enhance the anti-tumor activity of CAR-T.
At present, most co-stimulatory signals are transduced together with T cell receptor signals in the process of T cell activation, but in this study, researchers designed a co-stimulatory signal independent of T cell receptors, which can be activated alone to stimulate T cells. Researchers screened 12 co-stimulatory receptors, including ICOS, CD27, CD40L, and CD30, and found that OX40 had the most significant effect on CAR-T amplification.
OX40 is one of the important T cell costimulatory signals and a member of the tumor necrosis factor receptor (TNF) superfamily. OX40 ligand OX40L (also known as CD252) binds to three OX40 proteins in the form of trimer to form a hexamer complex, which activates downstream NF – κ B, PI3K, and AKT signaling pathways. 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 (Tregs), and enhance the killing ability of effector T cells.
In the experiment, the researchers also found that OX40 can reduce the apoptosis of CAR-T cells by up-regulating the gene expression of Bcl-2 family members, and enhance cell proliferation by increasing the activation of NF-κ B, MAPK, and PI3K-Akt signaling pathways. In addition, OX40 signaling not only enhances the cytotoxicity of CAR-T cells, but also reduces the failure markers, which can maintain the function of CAR-T cells in the immunosuppressive tumor microenvironment.
In vivo, OX40 co-stimulatory signal significantly enhanced the anti-tumor activity of CAR-T cells, and had a significant inhibitory effect on metastatic tumors, indicating that OX40 co-stimulatory signal is expected to be used in the treatment of solid tumors. Based on the method of this experiment, the autogenous 20BBZ-OX40 CAR-T therapy has entered the phase 1 clinical trial stage, which shows good tolerance and efficacy in patients with B-cell lymphoma.
In recent years, scientists have made considerable efforts to develop new methods to overcome solid tumor barriers, and adopt optimization strategies for CAR-T therapy for these specific indications. We are looking forward to demonstrating the real ability of CAR-T in the treatment of solid tumors as soon as possible with more and more technical and clinical breakthroughs.
Reference
Huihui Zhang, Fanlin Li, Jiang Cao, et al. A chimeric antigen receptor with antigen-independent OX40 signaling mediates potent antitumor activity. Sci Transl Med. 2021 Jan 27;13(578):eaba7308. doi: 10.1126/scitranslmed.aba7308.