A combined treatment regimen of MGMT-modified γδ T cells and temozolomide chemotherapy is effective against primary high grade gliomas

Chemotherapeutic drugs such as the alkylating agent Temozolomide (TMZ), in addition to reducing tumor mass, can also sensitize tumors to immune recognition by transient upregulation of multiple stress induced NKG2D ligands (NKG2DL). However, the potential for an effective response by innate lymphocyte effectors such as NK and gamma delta T cells that recognize NKG2DL is limited by the drug's concomitant lymphodepleting effects. We have previously shown that modification of gamma delta T cells with a methylguanine DNA methyltransferase (MGMT) transgene confers TMZ resistance via production of O-6-alkylguanine DNA alkyltransferase (AGT) thereby enabling gamma delta T cell function in therapeutic concentrations of TMZ. In this study, we tested this strategy which we have termed Drug Resistant Immunotherapy (DRI) to examine whether combination therapy of TMZ and MGMT-modified gamma delta T cells could improve survival outcomes in four human/mouse xenograft models of primary and refractory GBM. Our results confirm that DRI leverages the innate response of gamma delta T cells to chemotherapy-induced stress associated antigen expression and achieves synergies that are significantly greater than either individual approach.

Automated summary

The study confirmed the significant success of using "Drug Resistant Immunotherapy" (DRI) in the treatment of glioblastoma, showing that the combination therapy of MGMT-modified gamma delta T cells with TMZ can improve survival outcomes. This method leverages the innate response of gamma delta T cells to chemotherapy-induced stress associated antigen expression, resulting in synergies significantly greater than either individual approach.