Abstract 2020: A platform to test multiple therapies simultaneously in the intact tumors of cancer patients: Initial clinical experience

Abstract

Abstract We report the initial clinical findings of a device platform to test multiple therapeutic options simultaneously in individual living tumors within a clinical patient population, detailing for the first time comparative effects of different drugs within individual intact tumors. Most early cancer drug discovery is performed under in vitro conditions in cell-based models that poorly represent the disease they are intended to represent and have a poor track record for predicting success in subsequent clinical trials. To enable in vivo analysis of anti-cancer agent efficacy at earlier stages of drug development, and to potentially enable toxicity-sparing assessment of novel agents in the oncology clinic, we have developed a technology platform called CIVO™. CIVO allows for simultaneous assessment of up to eight drugs or drug combinations in a single solid tumor while the tumor is still in the patient. Controlled microinjection-based delivery of doxorubicin, docetaxel, mafosfamide, and gemcitabine was tested in twelve patients in the canine sarcoma clinic. Drugs were co-injected in a columnar array with UV fluorescent beads resulting in easy-to-identify bands of drug at 95% of the injection sites, each at a distinct position of the patient's tumor. Tumors were resected 72h following microinjection and were subjected to multiplexed analyses for tumor response which included drug-induced ablation of sarcoma cells, apoptosis, DNA damage, mitotic arrest, immune infiltration, and feedback activation of oncogenic pathways. The CIVO-introduced drug microdoses induced spatially-defined graded, and mechanism-specific cellular changes around sites of drug exposure in a drug and patient-specific manner. 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 (6/9 patients) exceeded those of all other agents tested, with Docetaxel being next most effective (2/6 patients), and Gemcitabine being the least effective (0/9 patients). Interestingly, almost all confirmed sites of response showed evidence of mTOR pathway upregulation, suggesting that mTOR pathway activation represents a potential common mechanism of chemo-resistance across sarcoma patients exists to multiple chemo-toxic agents. We are currently exploring combinations of 1st line sarcoma drugs with mTOR inhibitors in the canine sarcoma clinic with CIVO. This data represents the first time differential effects of multiple drugs have been captured within individual intact tumors in a clinical population. Along with early responses observed in the human clinic, this sets the stage for application of this technology to identify which novel agents are likely to succeed or fail in subsequent clinical trials. Citation Format: Alicia Moreno Gonzalez, Jason Frazier, William Kerwin, Jessica Bertout, Joseph Casalini, Sally Ditzler, Nathan Caffo, Richard A. Klinghoffer. A platform to test multiple therapies simultaneously in the intact tumors of cancer patients: Initial clinical experience. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2020. doi:10.1158/1538-7445.AM2015-2020