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Recombinant cytokines have limited anticancer efficacy mostly due to a narrow therapeutic window and systemic adverse effects. IL18 is an inflammasome-induced proinflammatory cytokine, which enhances T- and NK-cell activity and stimulates IFNγ production. The activity of IL18 is naturally blocked by a high-affinity endogenous binding protein (IL18BP). IL18BP is induced in the tumor microenvironment (TME) in response to IFNγ upregulation in a negative feedback mechanism. In this study, we found that IL18 is upregulated in the TME compared with the periphery across multiple human tumors and most of it is bound to IL18BP. Bound IL18 levels were largely above the amount required for T-cell activation in vitro, implying that releasing IL18 in the TME could lead to potent T-cell activation. To restore the activity of endogenous IL18, we generated COM503, a high-affinity anti-IL18BP that blocks the IL18BP:IL18 interaction and displaces precomplexed IL18, thereby enhancing T- and NK-cell activation. In vivo, administration of a surrogate anti-IL18BP, either alone or in combination with anti-PD-L1, resulted in significant tumor growth inhibition and increased survival across multiple mouse tumor models. Moreover, the anti-IL18BP induced pronounced TME-localized immune modulation including an increase in polyfunctional nonexhausted T- and NK-cell numbers and activation. In contrast, no increase in inflammatory cytokines and lymphocyte numbers or activation state was observed in serum and spleen. Taken together, blocking IL18BP using an Ab is a promising approach to harness cytokine biology for the treatment of cancer., (©2024 The Authors; Published by the American Association for Cancer Research.)

Background: There are various traditional landmarks used to estimate the femoral component version, yet none are widely accepted by direct anterior surgeons. The purpose of this study was to compare bony landmarks easily accessible to direct anterior surgeons and to estimate which one provides the best estimate of femoral component anteversion., Methods: A computed tomography database was used to identify 736 left entire-femur computed tomography scans. Seven visible anatomic landmarks were identified using a computer model in which a 45° virtual neck resection was made at 10 mm above the lesser trochanter. Thirteen axes, to reference the femoral stem position, were created between the 7 landmarks. Means and standard deviations (SDs) of angles between each axis and the transepicondylar axis (TEA) were compared for their precision., Results: The traditional lesser trochanter predicted anteversion from the TEA was 34.1° (SD 9.7°). Predicted anteversion from the TEA was 3.3° (SD 8.1°) when aligned from the center of the canal to the middle of the medial calcar; 14.0° (SD 8.1°) from the center of the canal to the anterior 1/3 of the medial calcar; and 24.8° (SD 8.5°) from the center of the canal to the most anterior point on the medial calcar., Conclusions: Compared to the lesser trochanter, 7 axes were more precise (lower SD) when predicting the version. Estimating the femoral component position, via simulated data, using 3 points along the medial calcar is a relatively precise and easily accessible tool for surgeons., (© 2024 The Authors.)