The T Cell Immunoscore as a Reference for Biomarker Development Utilizing Real-World Data from Patients with Advanced Malignancies Treated with Immune Checkpoint Inhibitors.

BACKGROUND: We aimed to determine the prognostic value of an immunoscore reflecting CD3+ and CD8+ T cell density estimated from real-world transcriptomic data of a patient cohort with advanced malignancies treated with immune checkpoint inhibitors (ICIs) in an effort to validate a reference for future machine learning-based biomarker development. METHODS: Transcriptomic data was collected under the Total Cancer Care Protocol (NCT03977402) Avatar® project. The real-world immunoscore for each patient was calculated based on the estimated densities of tumor CD3+ and CD8+ T cells utilizing CIBERSORTx and the LM22 gene signature matrix. Then, the immunoscore association with overall survival (OS) was estimated using Cox regression and analyzed using Kaplan-Meier curves. The OS predictions were assessed using Harrell's concordance index (C-index). The Youden index was used to identify the optimal cut-off point. Statistical significance was assessed using the log-rank test. RESULTS: Our study encompassed 522 patients with four cancer types. The median duration to death was 10.5 months for the 275 participants who encountered an event. For the entire cohort, the results demonstrated that transcriptomics-based immunoscore could significantly predict patients at risk of death (p-value < 0.001). Notably, patients with an intermediate-high immunoscore achieved better OS than those with a low immunoscore. In subgroup analysis, the prediction of OS was significant for melanoma and head and neck cancer patients but did not reach significance in the non-small cell lung cancer or renal cell carcinoma cohorts. CONCLUSIONS: Calculating CD3+ and CD8+ T cell immunoscore using real-world transcriptomic data represents a promising signature for estimating OS with ICIs and can be used as a reference for future machine learning-based biomarker development.

A cooperative game solution approach for intensity modulated radiation therapy design: Nash Social Welfare optimization.

We study the fluency map optimization problem in Intensity Modulated Radiation Therapy from a cooperative game theory point of view. We consider the cancerous and healthy organs in a patient's body as players of a game, where cancerous organs seek to eliminate the cancerous cells and healthy organs seek to receive no harm. The goal is to balance the trade-offs between the utility of players by forming a grand coalition between them. We do so by proposing a methodology that solves a few convex optimization problems in order to transform the fluency map optimization problem into a bargaining game. To solve the bargaining game, we employ the concept of Nash Social Welfare (NSW) optimization due to the desirable efficiency and fairness properties of its outcomes. The proposed NSW optimization is convex and can be solved by powerful commercial solvers such as CPLEX. An additional advantage of the proposed approach is that it has a new control lever for the fluency map optimization, the so-called negotiation powers, which enables practitioners to put more emphasis on an organ by changing its negotiation power. To show the efficacy of our proposed methodology, we apply it to the TG-119 case and a liver case. We compare our proposed approach with a state-of-the-art approach through creating Dose Volume Histograms.