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

• Published in: Scientific reports Vol. 11; no. 1; pp. 21133 - 8
• Main Authors: Lamb, Lawrence S., Pereboeva, Larisa, Youngblood, Samantha, Gillespie, G. Yancey, Nabors, L. Burton, Markert, James M., Dasgupta, Anindya, Langford, Catherine, Spencer, H. Trent
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 26-10-2021; Nature Publishing Group; Nature Portfolio
• Subjects: 631/250; 631/61/201; 631/61/2035; 631/61/2296; 631/61/24; 631/67; 692/4028; Animal models; Animals; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - therapy; Chemotherapy; Combined treatment; Deoxyribonucleic acid; DNA; DNA alkyltransferase; DNA methyltransferase; Drug resistance; Glioma; Glioma - metabolism; Glioma - pathology; Glioma - therapy; Humanities and Social Sciences; Humans; Immunosuppressive agents; Immunotherapy; Lymphocytes; Lymphocytes T; Methylguanine; Mice; Mice, Nude; multidisciplinary; O-Methylguanine-DNA Methyltransferase - biosynthesis; O-Methylguanine-DNA Methyltransferase - economics; O6-methylguanine-DNA methyltransferase; Receptors, Antigen, T-Cell, gamma-delta; Science; Science (multidisciplinary); T-Lymphocytes - enzymology; T-Lymphocytes - transplantation; Temozolomide; Temozolomide - pharmacology; Transgenes; Tumors; Xenograft Model Antitumor Assays; Xenografts
• ISSN: 2045-2322; 2045-2322
• DOI: 10.1038/s41598-021-00536-8

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 γδ T cells that recognize NKG2DL is limited by the drug’s concomitant lymphodepleting effects. We have previously shown that modification of γδ T cells with a methylguanine DNA methyltransferase (MGMT) transgene confers TMZ resistance via production of O
6
-alkylguanine DNA alkyltransferase (AGT) thereby enabling γδ 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 γδ 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 γδ T cells to chemotherapy-induced stress associated antigen expression and achieves synergies that are significantly greater than either individual approach.