IL15 modification enables CAR T cells to act as a dual targeting agent against tumor cells and myeloid-derived suppressor cells in GBM.

INTRODUCTION: The immunosuppressive tumor microenvironment (TME) is a major barrier to the efficacy of chimeric antigen receptor T cells (CAR-T cells) in glioblastoma (GBM). Transgenic expression of IL15 is one attractive strategy to modulate the TME. However, at present, it is unclear if IL15 could be used to directly target myeloid-derived suppressor cells (MDSCs), a major cellular component of the GBM TME. Here, we explored if MDSC express IL15Rα and the feasibility of exploiting its expression as an immunotherapeutic target. METHODS: RNA-seq, RT-qPCR, and flow cytometry were used to determine IL15Rα expression in paired peripheral and tumor-infiltrating immune cells of GBM patients and two syngeneic murine GBM models. We generated murine T cells expressing IL13Rα2-CARs and secretory IL15 (CAR.IL15s) or IL13Rα2-CARs in which IL15 was fused to the CAR to serve as an IL15Rα-targeting moiety (CAR.IL15f), and characterized their effector function in vitro and in syngeneic IL13Rα2+glioma models. RESULTS: IL15Rα was preferentially expressed in myeloid, B, and dendritic cells in patients' and syngeneic GBMs. In vitro, CAR.IL15s and CAR.IL15f T cells depleted MDSC and decreased their secretion of immunosuppressive molecules with CAR.IL15f T cells being more efficacious. Similarly, CAR.IL15f T cells significantly improved the survival of mice in two GBM models. TME analysis showed that treatment with CAR.IL15f T cells resulted in higher frequencies of CD8+T cells, NK, and B cells, but a decrease in CD11b+cells in tumors compared with therapy with CAR T cells. CONCLUSIONS: We demonstrate that MDSC of the glioma TME express IL15Ra and that these cells can be targeted with secretory IL15 or an IL15Rα-targeting moiety incorporated into the CAR. Thus, IL15-modified CAR T cells act as a dual targeting agent against tumor cells and MDSC in GBM, warranting their future evaluation in early-phase clinical studies.

Second-generation porous-coated cementless total hip arthroplasties have high survival.

We retrospectively reviewed 157 consecutive total hip arthroplasties performed with Prodigy stems and Duraloc cups to see whether design modifications made to these components would improve their clinical performance as compared with first-generation porous-coated components. At an average of 6.7 years postoperatively, 145 hips were available for followup. The data suggested encouraging clinical and radiographic performances for these second-generation components. With only two hips (1.4%) in this population being revised, survivorship analysis was 99% 5 years postoperatively. Bone ingrowth was evident in 99% of the stems, and all cups were stable at last followup. Large osteolytic lesions were observed in three acetabula and seven femurs with all femoral lesions being confined to the proximal Gruen Zones 1 or 7. Polyethylene wear averaged 0.10 +/- 0.14 mm/year. Ninety-eight percent of patients reported satisfaction with the procedure, and 7% reported activity-limiting pain. Early followup of the Prodigy-Duraloc combination in primary cementless total hip arthroplasties showed the Prodigy stem had similarly good clinical results compared with its predecessor, the AML stem, and the Duraloc cup was superior to its first-generation predecessor, the anatomic medullary locking cup with Acetabular Cup System (ACS) liner.