RESUMEN
Introduction: Drug development is systemically inefficient. Research and development costs for novel therapeutics average hundreds of millions to billions of dollars, with the overall likelihood of approval estimated to be as low as 6.7% for oncology drugs. Over half of these failures are due to a lack of drug efficacy. This pervasive and repeated low rate of success exemplifies how preclinical models fail to adequately replicate the complexity and heterogeneity of human cancer. Therefore, new methods of evaluation, early in the development trajectory, are essential both to rule-in and rule-out novel agents with more rigor and speed, but also to spare clinical trial patients from the potentially toxic sequelae (high risk) of testing investigational agents that have a low likelihood of producing a response (low benefit). Methods: The clinical in vivo oncology (CIVO®) platform was designed to change this drug development paradigm. CIVO precisely delivers microdose quantities of up to 8 drugs or combinations directly into patient tumors 4-96 h prior to planned surgical resection. Resected tissue is then analyzed for responses at each site of intratumoral drug exposure. Results: To date, CIVO has been used safely in 6 clinical trials, including 68 subjects, with 5 investigational and 17 approved agents. Resected tissues were analyzed initially using immunohistochemistry and in situ hybridization assays (115 biomarkers). As technology advanced, the platform was paired with spatial biology analysis platforms, to successfully track anti-neoplastic and immune-modulating activity of the injected agents in the intact tumor microenvironment. Discussion: Herein we provide a report of the use of CIVO technology in patients, a depiction of the robust analysis methods enabled by this platform, and a description of the operational and regulatory mechanisms used to deploy this approach in synergistic partnership with pharmaceutical partners. We further detail how use of the CIVO platform is a clinically safe and scientifically precise alternative or complement to preclinical efficacy modeling, with outputs that inform, streamline, and de-risk drug development.
RESUMEN
Acute invasive fungal sinusitis (AIFS) classically presents as an aggressive fungal infection that can spread beyond its origin in the sinuses in immunocompromised patients. Although there have been reports of AIFS in immunocompetent, non-diabetic patients, it is extremely rare and the true mechanism behind it is unknown. A thirty-eight year old immunocompetent, non-diabetic woman underwent bilateral ESS for chronic rhinosinusitis with nasal polyps at a tertiary care center and post-operatively developed AIFS. Patient underwent uncomplicated ESS, was packed with foam containing triamcinolone and discharged on steroid rinses and a prednisone taper. Surgical pathology demonstrated left-sided colonization with non-invasive fungal elements consistent with a mycetoma. She presented on post-operative Day 11 with headache and left-sided retro-orbital pain. A culture of her left nasal cavity grew Rhizopus spp and MRI demonstrated evidence of invasive fungal infection of left sphenoid mucosa as well as inflammatory changes in the left orbit centered at the orbital apex. She was started on amphotericin and underwent a left-sided debridement with biopsies which demonstrated angioinvasive fungal disease. Her vision in her left eye worsened to 20/800 and she was treated with transcutaneous retrobulbar injection of amphotericin B. After stable interval imaging she was discharged on a long-term course of antifungals. Extensive immunologic work-up was unremarkable. We describe a case of an immunocompetent patient who developed AIFS after sinus surgery for CRS and a mycetoma likely as a result of local immune suppression and post-surgical trauma. Laryngoscope, 2024.
