Department of Biomedical Engineering; University of Arkansas ; Fayetteville, AR USA.
Oncoimmunology. 2015 Jan 7;3(12):e968001. doi: 10.4161/21624011.2014.968001. eCollection 2014 Dec.
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-γ production. Cell-mediated immune memory was confirmed 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.
转移约占乳腺癌相关死亡的 90%。因此，预防或控制乳腺癌转移的新方法具有重要的临床意义。基于白细胞介素-12（IL-12）的免疫疗法已显示出控制转移性疾病的潜力，但由于早期试验中 IL-12 的全身给药导致反应适度和严重毒性，阻碍了其临床应用。我们假设局部给予与壳聚糖（壳聚糖/IL-12）共配制的 IL-12 可以引发肿瘤特异性免疫，并提供针对转移性乳腺癌的全身保护，同时最大限度地减少全身毒性。壳聚糖是一种主要来源于甲壳类动物外骨骼的生物相容性多糖。在临床相关的切除模型中，患有自发性转移性 4T1 乳腺腺癌的小鼠在肿瘤切除前接受壳聚糖/IL-12 或适当对照的瘤内注射。与单独使用 IL-12 或壳聚糖的小鼠相比，壳聚糖/IL-12 新辅助免疫治疗使 67%的小鼠实现了长期无肿瘤存活，而单独使用 IL-12 或壳聚糖的小鼠分别为 24%或 0%。壳聚糖/IL-12 治疗后的抗肿瘤反应持久，并为用 4T1 而不是 RENCA 肾腺癌细胞再次攻击提供了完全保护。壳聚糖/IL-12 治疗后的淋巴细胞表现出强大的肿瘤特异性裂解活性和干扰素-γ产生。通过临床相关的迟发型超敏反应（DTH）测定证实了细胞介导的免疫记忆。全面的血液学和毒理学分析显示，壳聚糖/IL-12 诱导短暂、可逆的白细胞减少，而关键器官功能无变化。这项研究的结果表明，在乳房肿瘤切除前进行壳聚糖/IL-12 新辅助免疫治疗是一种有前途的可转化策略，能够安全地诱导肿瘤特异性免疫，并从长远来看降低因进行性复发而导致的乳腺癌死亡率。
