Discussion
tumor, cancer, inflammation, high-grade glioma, tumors
DISEASE PROGRESSION, TUMOR, INFILTRATION, CANCER, DISEASE, TRIPLE-NEGATIVE BREAST CANCER, INFLAMMATION, ADVERSE EFFECTS, TUMOR PROGRESSION, INFILTRATING, TUMORS, INFILTRATED
We conducted an in-human pilot study of 4SCAR-T cells targeting GD2 in eight patients with GD2 positive GBM. In this study, the safety of autologous GD2-specific 4SCAR-T cells was assessed in eight patients with progressive GBM. No severe adverse effects were observed in the patients receiving GD2-specific 4SCAR-T cell infusion. CAR-T cells expanded and peaked at 1–3 weeks after infusion. Of the eight evaluable patients, five patients had a clinical benefit as defined by a partial response and stable disease. Three patients with clinical benefits were alive after more than 12 months of follow-up. The median overall survival of this study was 10 months after 4SCAR-T cell infusion (range, 3–24 months).The trafficking of CAR-T cells to tumors is a major challenge for GBM treatment, and the route of infusion appears to be important. Reports show that different infusion routes including intravenous, intracavitary, and intraventricular injections have been attempted for GBM CAR-T therapies, although intravenous injection is commonly used. Although intracavitary and intraventricular injections require implantation of the Rickham device, these routes enable the trafficking of CAR-T cells into tumor sites of the central nervous system [The major observation from this study was the effect of 4SCAR-T cells on the tumor immune microenvironment. We observed that there were a large number of T cells and macrophages infiltrating the tumor resected after GD2-specific 4SCAR-T cell infusion. In situ phenotypic analysis of post-infusion T cells showed that the infiltrated T cells were CD8 + T cells. In addition, fewer CD163 + M2 macrophages were detected in post-infusion tumor specimens. These findings suggest that infused 4SCAR-T cells stimulate the immune response in the tumor microenvironment.Infused GD2-specific 4SCAR-T cells could potentially recognize GD2 antigen expressed in GBM and exert tumor-killing functions. In one patient whose tumor was resected 6 weeks after infusion, we found that GD2 antigen expression dramatically decreased in GBM specimens post-infusion. The up-regulated expression of GD2 antigen in cancer cells was reported to be related with NF-κB and its biosynthesis was regulated by GD3 synthase (ST8SIA1), especially in the model of triple-negative breast cancer [Despite these advances, there are several limitations. MRI is a standard approach for assessing tumor progression and response in GBM. However, we observed that MRI could not effectively distinguish pseudo-progression and true disease progression in this study. In our case, we observed immune cell infiltration and inflammation in the tumor after 4SCAR-T administration, which often resulted in pseudoprogression and could affect the assessment of tumor progression. A similar observation was reported in a previous clinical study, which showed infused EGFRvIII-specific CAR-T cells in patients with progressive GBM [The sample size of our study is limited, thus definitive conclusions on the clinical benefits cannot be drawn yet. A previous study demonstrated that children (< 18 years) with high-grade glioma have a better prognosis than adults [