A window of opportunity trial using intratumoral injection of glatiramer as an immune modulator in patients with resectable head and neck and cutaneous squamous cell cancer

BACKGROUND: Immunotherapy using checkpoint inhibition improves outcome of patients with melanoma, lung, bladder, microsatellite instability-high and other tumors[1]. However, systemic administration of immunotherapy may have limited activity in some tumors partly due to failure of activated T cells to migrate to tumor[1]. Intratumoral injections (ITI) may allow high concentration of immunostimulatory products locally while using small amounts of drugs. This may also facilitate multiple combination therapies and avoid systemic off-target toxicities. By capitalizing on existing data and experience, repurposing approved drugs for cancer represents an opportunity to rapidly advance promising therapies. Glatiramer acetate is an agent commonly used for multiple sclerosis[2]. It acts as an immunomodulator and has essentially no systemic bioavailability but exhibits a high prevalence of injection site reactions[2]. It upregulates the activity of natural killer cells in leukemia cell lines [3], suggesting potential for immunostimulatory effect for ITI. For percutaneously accessible tumors for which the standard of care is surgical resection without any neoadjuvant therapy, there exists a window of opportunity where ITI of glatiramer can be performed before surgery. METHODS: This is a proof-of-concept, investigator-initiated, window of opportunity trial in subjects with percutaneously accessible head and neck or cutaneous squamous cell cancer who are to undergo surgery. Subjects will receive glatiramer 40 mg by ITI 3 times a week prior to surgery. Subjects will receive at least one dose and up to 3 doses of glatiramer. About 10 eligible patients will be included in this trial. Safety data will be collected. Tumor tissue at the time of diagnosis and at the time of surgery will be collected and compared for biomarkers. Primary endpoint is safety. Secondary endpoint is effect of ITI of glatiramer on biomarker levels. Pre- and post-treatment tumor samples will be tested using an immunology panel that profiles immunology genes and proteins including major classes of cytokines, interferons, KIR family, and TNF-receptor. Tumors samples will also be evaluated for the Ki-67 proliferative index and for caspase-3 and cleaved caspase-3 immunoexpression. Paired T-test or the Wilcoxon signed rank test will be used to assess the changes in the variables. We hypothesize that this approach will break the immunosuppressive tumor microenvironment as evidenced by an increase in inflammatory cytokines, chemokines, and immune cell infiltration. Decline in Ki-67 and increase in caspase-3 may be a signal of anti-tumor activity. TRIAL REGISTRATION: NCT03982212