Research Article: Central memory-enriched V?9V?2 ?? T cells via TGF-? expansion demonstrate enhanced in vivo efficacy against metastatic osteosarcoma
Abstract:
The application of cellular immunotherapies (CI) for osteosarcoma (OS) has mainly focused on autologous products of ?? T cells and, to date, has shown little clinical benefit. Based on the multi-killing properties of ?? T cells, specifically V?9V?2 T cells, and their ability to be employed as an allogeneic, off-the-shelf cellular therapy, there is significant interest in this CI. Although there are efficient, clinical-scale expansion protocols, a concern is the short in vivo half-life of these cells due to the terminal differentiated phenotypes of expanded cells. Therefore, modifying the manufacturing process to generate a more memory-like phenotype could overcome hurdles associated with this CI. Transforming growth factor-beta (TGF-?) is a cytokine with multiple functions, and can induce a less differentiated phenotype in ?? T cells. We tested the hypothesis that the in vivo effectiveness of ?? T cells against osteosarcoma (OS) tumors is suboptimal because of the manufacturing process that produces terminally differentiated cells. We combined a modified expansion process with activation strategies known to enhance ?? T cell-based tumor killing. Introducing zoledronate (ZOL) to OS cells augments ?? T cell killing by upregulating phosphoantigens in treated cells, which induces butyrophilin complexes, which are recognized by the TCR of the ?? T cell and significantly increases target cell death in both control and TGF-? expanded ?? T cells. In addition, administering ifosfamide (IFO), a chemotherapy used for relapsed OS, induces stress antigens in OS cell lines that are recognized by NKG2D receptors on ?? T cells, which enhances ?? T cell killing. In vivo studies show the administration of TGF-? expanded ?? T cells, when combined with ZOL and IFO significantly increased overall survival in OS-bearing mice, which we show can be attributed, at least in part, to increased persistence compared to control cells. Together, these data demonstrate this chemoimmunotherapy strategy, which engages various targeting mechanisms of ?? T cells, significantly enhances killing of OS.
Introduction:
Osteosarcoma (OS) is among the deadliest pediatric cancers with a survival rate of 27% in high-risk, distal, or Stage 4, patients ( 1 ). OS is the most common primary malignant pediatric bone tumor with a worldwide incidence of 3.4 per million people ( 2 ). Approximately 1 in 5 OS patients at first diagnosis have metastatic disease or are at the distal stage ( 1 ). The standard-of-care for OS requires a complex, multidisciplinary regimen for treatment, involving chemotherapy and surgery ( 3 ). However, in recent…
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