Pilot phase I trial of an implantable microdevice for in vivo evaluation of drug response in renal cell carcinoma.

Abstract

540 Background: Optimal treatment selection in renal cell carcinoma (RCC) remains challenging, but individual biomarkers based on tumor biology may enable personalized therapy and improve patient outcomes. We developed implantable microdevices (IMD) that can be placed into target tumors through a standard small-gauge interventional needle under imaging guidance. The IMDs deliver spatially segregated microdoses of up to 20 different locally administered drugs, including targeted, cytotoxic, and immunomodulatory agents, and/or combinations into the surrounding tumor tissue. Drug responses can be assessed within the tumor microenvironment without exposing the patient to systemic drug toxicity. Methods: Eligible patients had suspected or confirmed RCC planned for standard-of-care surgical resection of primary or metastatic tumors. Three (±1) days before surgery, one or more IMDs were percutaneously implanted into target lesions under CT guidance. At nephrectomy or metastasectomy, IMDs and adjacent tumor tissue were excised en bloc and fixed, embedded, and sectioned. Downstream analysis included H&E stainings, immunohistochemistry (IHC) for apoptotic and VEGF pathway markers, cyclic immunofluorescence (cycIF) with a 25-marker panel for proliferation, apoptosis, and immune cell profiling, and spatial transcriptomics. Patients subsequently received standard systemic therapy at their oncologist’s discretion. Co-primary endpoints were safety (defined as ≤1 safety failures) and feasibility (defined as sufficient tissue for histopathological analysis of ≥50% of IMD wells). Results: Ten patients were enrolled including 7 clear cell and 3 non-clear cell RCCs. At time of IMD implantation, 50% had been pre-treated with checkpoint inhibitors and/or targeted therapy. A total of 33 IMDs were implanted into six primary tumors, three metastases, and one local recurrence in the nephrectomy bed. All IMDs were retrieved at surgery and 25 IMDs (75.8%) remained embedded in tissue after processing. Feasibility and safety endpoints were met with no safety events reported. IHC for cleaved caspase-3 showed drug-dependent patterns of apoptosis and spatial variation relative to the distance from the IMD. Differential immune cell compositions in the drug-exposed regions were identified by cycIF. Spatial transcriptomics delineated drug class effects on molecular pathways within the tissue microenvironment. Conclusions: In our pilot phase 1 study, percutaneous CT-guided implantation of IMDs in patient RCC tumors was safe and feasible and revealed differential drug effects on apoptosis, proliferation, and immune cell composition. Clinical trial information: NCT05700461 .