Metastasis accounts for approximately 90% of breast cancer-related deaths. Therefore, novel approaches which prevent or control breast cancer metastases are of significant clinical interest. Interleukin-12 (IL-12)-based immunotherapies have shown promise in controlling metastatic disease, yet modest responses and severe toxicities due to systemic administration of IL-12 in early trials have hindered clinical application. We hypothesized that localized delivery of IL-12 co-formulated with chitosan (chitosan/IL-12) could elicit tumor-specific immunity and provide systemic protection against metastatic breast cancer while minimizing systemic toxicity. Chitosan is a biocompatible polysaccharide derived primarily from the exoskeletons of crustaceans. In a clinically relevant resection model, mice bearing spontaneously metastatic 4T1 mammary adenocarcinomas received intratumoral injections of chitosan/IL-12, or appropriate controls, prior to tumor resection. Neoadjuvant chitosan/IL-12 immunotherapy resulted in long-term tumor-free survival in 67% of mice compared to only 24% or 0% of mice treated with IL-12 alone or chitosan alone, respectively. Antitumor responses following chitosan/IL-12 treatment were durable and provided complete protection against rechallenge with 4T1, but not RENCA renal adenocarcinoma, cells. Lymphocytes from chitosan/IL-12-treated mice demonstrated robust tumor-specific lytic activity and interferon-g production. Cell-mediated immune memory was confirmed in vivo via clinically relevant delayed-type hypersensitivity (DTH) assays. Comprehensive hematology and toxicology analyses revealed that chitosan/IL-12 induced transient, reversible leukopenia with no changes in critical organ function. Results of this study suggest that neoadjuvant chitosan/IL-12 immunotherapy prior to breast tumor resection is a promising translatable strategy capable of safely inducing to tumor-specific immunity and, in the long term, reducing breast cancer mortality due to progressive recurrences.

Bacteriophage Survivors is a siphovirus isolated from Gordonia rubripertincta NRRL B-16540. Survivors has a 45,436-bp genome encoding 69 predicted protein-coding genes, of which 32 have assigned functions. Based on gene content similarity to sequenced actinobacteriophages, Survivors is assigned to phage cluster CT.

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Interleukin-12 (IL-12) is a potent antitumor cytokine that exhibits significant clinical toxicities after systemic administration. Local delivery of IL-12 has been shown to significantly reduce this threat. Our lab has recently shown that local delivery of IL-12 with the biopolymer chitosan can eliminate aggressive murine tumors while minimizing the chances for toxicity. In addition to eliminating the tumors, our lab has demonstrated that local chitosan/IL-12 immunotherapy can lead to the activation and expansion of CD8+ T cells and natural killer cells, increased production of interferon-gamma, and activation of dendritic cells that can recognize and attack these tumor cells. This immune response was evaluated for efficacy in preventing tumor metastasis. Mice bearing 4T1 tumors were treated with DPBS, IL-12, chitosan, or chitosan-IL-12 prior to surgical resection of the primary tumor. Survival analysis returned survival rates of 0%, 25%, 0%, and 40% respectively. In a separate study, lungs were examined for metastatic nodules revealing that mice treated with chitosan/IL-12 displayed significantly fewer nodules than other treatment groups. Based on the data obtained thus far, chitosan/IL-12 shows promising potential as an immunotherapy to reduce metastatic disease. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1535. doi:1538-7445.AM2012-1535