Investigators have developed a line of genetically modified T cells that specifically target and destroy human glioma tumors transplanted into the brains of mice. They now seek to improve the long-term efficacy of this treatment by further modifying the T cells and their mode of administration.
One mode of cancer immunotherapy is to inject tumors with cytotoxic T cells that recognize tumor cells and destroy them. In previous work, the investigators had preliminary success in treating glioblastoma multiforme (GBM) tumors using genetically modified T cells called “HER2-T cells.” These T cells bear receptors for human epidermal growth factor receptor 2 (HER2). This is a protein that is expressed at abnormally high levels by GBM tumor cells, and so these HER2-T cells are able to bind selectively to tumor cells. In addition, the HER2 receptor on these T cells is engineered to include signaling areas (regions of the receptor that lie inside the cell) that activate the T cells after they bind to tumor cells, causing the HER2-T cells to proliferate and kill the tumor cells.
When HER2-T cells were injected into human GBM tumors that had been transplanted into the brains of mice, they destroyed the tumors. Nonetheless, tumors later reappeared in the mice. The investigators suspect that tumor reappearance might be due to one or several factors, including: (1) failure of the HER2-T cells to proliferate and remain active at the site of the injection; (2) failure of the HER2-T cells to migrate to and destroy small groups of tumor cells lying at a distance from the injection site; or (3) suppression of HER2-T cell activity by tumor cell-secreted factors.
The investigators will address each of these possibilities through specific modifications of their therapeutic design. First, they will add to the engineered HER2 receptor another T cell-activating area and assess its effect on T cell proliferation and killing of GBM cells in laboratory cultures and in vivo. Second, they will try to improve the migratory capacity of the HER2-T cells. Third, they will determine whether HER2-T cell proliferation and killing of GBM cells in laboratory cultures and in vivo is enhanced by a drug that inhibits a specific protein, which is produced at high levels in GBM cells and promotes their secretion of immunosuppressant cytokines.
Significance: This study will advance the development of more sophisticated T cell therapies for a particularly aggressive form of human brain tumor, for which no treatments with long-term efficacy currently exist.