2510 - Leveraging Nanomechanical Signatures as Predictive Biomarkers for Radiation Therapy Guidance in Advanced Solid Tumors

Purpose/Objective(s): Radiation treatment of solid tumors has traditionally focused on direct cytotoxicity through clinical radiation protocols. Recent advancements have prompted the exploration of low-dose radiation (LD-XRT) strategies, aimed at enhancing efficacy and reducing toxicity, potentially transforming patient outcomes, especially in advanced solid tumors. We evaluated the role of the nanomechanical signature (NS) as a pivotal advancement in the assessment and prediction of tumor response to combination LD-XRT and immunotherapy treatment modalities. The NS provides biomechanical properties of the tumor microenvironment (TME). Our hypothesis is that this signature could serve as a new class of robust, tumor-agnostic biomarkers by detecting unique biomechanical shifts due to stroma remodulation and immune activation. With seamless integration in the clinical workflows, NS biomarkers promise to not only enhance the accuracy of predicting patient responses to low-dose radiation therapy combined with immunotherapy, but also facilitate improve stratification of patients, ultimately contributing to personalized and effective treatment strategies in advanced solid tumors.

Materials/Methods: To characterize nanomechanical signatures, the ARTIDIS platform, based on Atomic Force Microscopy technology, is utilized to non-disruptively assess biomechanical profile of fresh tumor specimens. Patients with extensive liver and lung metastasis from solid tumors were co-enrolled in the ongoing salvage radiation study (NCT02710253), and the ARTIDIS Umbrella protocol within the same US-based cancer center. Two preclinical models were further explored to investigated the mechanisms of restored response, namely a PD1-resistant lung adenocarcinoma on 129Sv/Ev mice, and a gastric cancer on NSG mice, treated with anti-CTLA and anti-PD1 in combination with LD-XRT and anti-mesothelin CAR-T cell therapy in combination with LD-XRT, respectively.

Results: Exploratory analysis of clinical cases enrolled to date confirms that a unique NS characterizes different combination radiotherapy/immunotherapy therapeutic regimens among similar clinical and histopathological cases. Our preclinical study on combination immune checkpoint inhibitors/low-dose therapy identifies the NS of response to immunotherapy upon priming with low-dose radiation and the NS of activated T cells with high sensitivity, specificity, and AUC (90%-99%).

Conclusion: We demonstrated across different radiotherapy strategies, preclinical tumor models and clinical case reports that NS can quantitatively describe TME remodulation and immune activation upon LD-XRT that mediates restored response to immunotherapy (immune checkpoint inhibitors and CAR-T cell therapy). These results support the use of NS as predictive biomarkers of response to combination low-dose radiotherapy and immunotherapy to support clinical decision-making, which is being further validated by on-going and planned studies.