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. 2024 Feb 7:15:1299044.
doi: 10.3389/fimmu.2024.1299044. eCollection 2024.

Adoptive cell therapy for high grade gliomas using simultaneous temozolomide and intracranial mgmt-modified γδ t cells following standard post-resection chemotherapy and radiotherapy: current strategy and future directions

L B Nabors  1 , L S Lamb  2 , T Goswami  2 , K Rochlin  2 , S L Youngblood  2
Affiliations

Adoptive cell therapy for high grade gliomas using simultaneous temozolomide and intracranial mgmt-modified γδ t cells following standard post-resection chemotherapy and radiotherapy: current strategy and future directions

L B Nabors et al. Front Immunol. .

Abstract

Cellular therapies, including chimeric antigen receptor T cell therapies (CAR-T), while generally successful in hematologic malignancies, face substantial challenges against solid tumors such as glioblastoma (GBM) due to rapid growth, antigen heterogeneity, and inadequate depth of response to cytoreductive and immune therapies, We have previously shown that GBM constitutively express stress associated NKG2D ligands (NKG2DL) recognized by gamma delta (γδ) T cells, a minor lymphocyte subset that innately recognize target molecules via the γδ T cell receptor (TCR), NKG2D, and multiple other mechanisms. Given that NKG2DL expression is often insufficient on GBM cells to elicit a meaningful response to γδ T cell immunotherapy, we then demonstrated that NKG2DL expression can be transiently upregulated by activation of the DNA damage response (DDR) pathway using alkylating agents such as Temozolomide (TMZ). TMZ, however, is also toxic to γδ T cells. Using a p140K/MGMT lentivector, which confers resistance to TMZ by expression of O(6)-methylguanine-DNA-methyltransferase (MGMT), we genetically engineered γδ T cells that maintain full effector function in the presence of therapeutic doses of TMZ. We then validated a therapeutic system that we termed Drug Resistance Immunotherapy (DRI) that combines a standard regimen of TMZ concomitantly with simultaneous intracranial infusion of TMZ-resistant γδ T cells in a first-in-human Phase I clinical trial (NCT04165941). This manuscript will discuss DRI as a rational therapeutic approach to newly diagnosed GBM and the importance of repeated administration of DRI in combination with the standard-of-care Stupp regimen in patients with stable minimal residual disease.

Keywords: DNA damage (DDR); T cells gamma delta; cell therapy; genetic engineering; glioblastoma.

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Conflict of interest statement

The concepts and work contained in this manuscript were conceived at the University of Alabama at Birmingham UAB by LL and licensed by IN8Bio at which LL has been employed as of 1 January 2019. KR, TG, and SY are also employees of IN8Bio, Inc. LN is faculty at UAB and has received funding from IN8Bio to conduct the referenced clinical trial as an IIT.

Figures

Figure 1
Figure 1
The Phase I Drug Resistant Immunotherapy trial is combined with the standard of care Stupp regimen consisting of resection + radiation/TMZ chemotherapy followed by six 28-day cycles of oral maintenance TMZ (A). For the DRI protocol (B) a Rickham catheter is inserted into the tumor cavity following resection. Peripheral blood mononuclear cells (PBMC) for manufacturing of the cell product 3-4 weeks following tumor resection and prior to induction chemotherapy and radiotherapy (see text). The MGMT-modified γδ T cell product is infused on the first day of each maintenance cycle (depending on cohort-see text) within 4h of intravenous TMZ. (C) outlines the strategy that informs the clinical trial in which the tumor mass is reduced to minimal residual disease, the DDR and subsequent upregulated stress antigen expression then activated by TMZ and simultaneously targeted with a high local dose of MGMT-modified γδ T cells. Oral TMZ dosing continues for the remaining 4 days of the cycle and then repeated to provide continued pressure on tumor survival and proliferation.
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