Development of a Curative Immunotherapeutic Strategy for the Treatment of Big Established CT26 Tumors

Abstract

Abstract Immunotherapy has demonstrated the ability to cause some complete clinical remissions even in patients with late stage cancers. However, currently used approaches fail in many cases. We hypothesize that a combination of promoting the generation of antitumor immune response and reverting the immunosuppressive environment of cancers would be more effective. In this study, we investigated the therapeutic effect of a combination of cytoxan and HMGN1 on established CT26 tumors. HMGN1 is a Th1-polarizing alarmin capable of promoting antitumor immune protection, whereas cytoxan (CY) reduces regulatory T cells. Treatment with one dose of CY and four doses of HMGN1 completely inhibited tumor growth in Balb/c mice bearing small CT26 tumors, but only partially in mice bearing big (≈1.0 cm diameter) tumors. To improve the efficiency, R848 was added to the treatment combination. The triple combination (‘TheraVac’) eradicated big CT26 tumors. Importantly, the resulting tumor-free mice were resistant to rechallenge with CT26, but not resistant to unrelated 4T1 tumors, indicating the development of protective anti-CT26 immunity. Profiling of tumor infiltrating leukocytes revealed that there was a reduction of dendritic cells and a concomitant increase in T cells in the tumor after TheraVac treatment. Thus, we have developed a curative immunotherapeutic strategy for big established CT26 tumors.