Toxicity-Sparing In-Tumor Profiling Of Multiple Drugs Simultaneously In Canine Patients With Sarcoma

e22177 Background: Cancer drug developers face a fundamental challenge in the way new candidate drugs are evaluated. Early stage compounds are tested in preclinical models that lack important components of the complex tumor microenvironment and poorly reflect disease seen in the clinic. To address this issue we present a technology called CIVO that demonstrates the potential for testing experimental compounds directly in tumors of cancer patients prior to entry into formal clinical trials. Methods: A two-stage feasibility study was performed in canine patients with sarcoma. In the first stage, localized tumor response to a set of four drugs commonly used in the soft-tissue sarcoma clinic including Doxorubicin, Mafosfamide (an active surrogate of the pro-drug Ifosfamide), Gemcitabine, and Docetaxel was evaluated. In the second stage, an additional novel compound (PS-1001) was evaluated and compared to the conventional agents. An eight-needle arrayed microinjection device delivered microdose amounts of each drug or compound to distinct and localized positions of the tumor. Forty-eight hours after injection, tumors were surgically removed and processed for immunohistochemistry-based biomarker analysis. Results: Consistent with the use of doxorubicin as first line therapy in the soft tissue sarcoma clinic, the frequency and extent of response of localized tumor kill induced by Doxorubicin (10/11 patients) exceeded those of all other agents tested. Furthermore, consistent with the ability to induce immunogenic cell death, Doxorubicin induced localized increases in CD3 positive T-cells and in polymorphonuclear neutrophils. None of the other conventional agents induced a consistent immune response. Tumor profiling of PS-1001 revealed unexpected robust increases in localized immune cell infiltrate including NK-cells and polymorphonuclear neutrophils (6/7 patients) that exceeded the immune response induced by Doxorubicin. No toxicity was observed in any patient according to VCOG Conclusions: CIVO technology has the potential for functionally profiling experimental compounds directly in the only truly accurate disease context, the cancer patient.