Zaharoff David A, Hoffman Benjamin S, Hooper H Brooks, Benjamin Compton J, Khurana Kiranpreet K, Hance Kenneth W, Rogers Connie J, Pinto Peter A, Schlom Jeffrey, Greiner John W
Laboratory of Tumor Immunology Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Cancer Res. 2009 Aug 1;69(15):6192-9. doi: 10.1158/0008-5472.CAN-09-1114. Epub 2009 Jul 28.
Intravesical BCG has been used successfully to treat superficial bladder cancer for three decades. However, 20% to 30% of patients will fail initial BCG therapy and 30% to 50% of patients will develop recurrent tumors within 5 years. Alternative or complementary strategies for the management of superficial bladder cancer are needed. Interleukin-12 (IL-12) is a potent T(H)1 cytokine with robust antitumor activity and the ability to potentiate immunologic memory. Unfortunately, intravesical IL-12 did not show antitumor efficacy in a recent clinical study of patients with recurrent superficial bladder cancer. We hypothesized that coformulation of IL-12 with chitosan, a biocompatible, mucoadhesive polysaccharide, could improve intravesical IL-12 delivery and provide an effective and durable alternative for the treatment of superficial bladder cancer. In antitumor studies, 88% to 100% of mice bearing orthotopic bladder tumors were cured after four intravesical treatments with chitosan/IL-12. In contrast, only 38% to 60% of mice treated with IL-12 alone and 0% treated with BCG were cured. Antitumor responses following chitosan/IL-12 treatments were durable and provided complete protection from intravesical tumor rechallenge. Urinary cytokine analysis showed that chitosan/IL-12 induced multiple T(H)1 cytokines at levels significantly higher than either IL-12 alone or BCG. Immunohistochemistry revealed moderate to intense tumor infiltration by T cells and macrophages following chitosan/IL-12 treatments. Bladder submucosa from cured mice contained residual populations of immune cells that returned to baseline levels after several months. Intravesical chitosan/IL-12 is a well-tolerated, effective immunotherapy that deserves further consideration for testing in humans for the management of superficial bladder cancer.
膀胱内灌注卡介苗（BCG）已成功用于治疗浅表性膀胱癌三十年。然而，20%至30%的患者初始BCG治疗会失败，30%至50%的患者会在5年内出现肿瘤复发。因此，需要用于治疗浅表性膀胱癌的替代或辅助策略。白细胞介素-12（IL-12）是一种强效的辅助性T细胞1（TH1）细胞因子，具有强大的抗肿瘤活性和增强免疫记忆的能力。遗憾的是，在最近一项针对复发性浅表性膀胱癌患者的临床研究中，膀胱内灌注IL-12并未显示出抗肿瘤疗效。我们推测，将IL-12与壳聚糖（一种生物相容性、粘膜粘附性多糖）共同配制，可以改善膀胱内IL-12的递送，并为浅表性膀胱癌的治疗提供一种有效且持久的替代方案。在抗肿瘤研究中，88%至100%的原位膀胱肿瘤小鼠在接受四次膀胱内注射壳聚糖/IL-12治疗后被治愈。相比之下，单独接受IL-12治疗的小鼠只有38%至60%被治愈，接受BCG治疗的小鼠无一被治愈。壳聚糖/IL-12治疗后的抗肿瘤反应具有持久性，并能完全保护小鼠免受膀胱内肿瘤再次攻击。尿细胞因子分析表明，壳聚糖/IL-12诱导的多种TH1细胞因子水平显著高于单独使用IL-12或BCG。免疫组织化学显示，壳聚糖/IL-12治疗后，T细胞和巨噬细胞对肿瘤有中度至强烈浸润。治愈小鼠的膀胱粘膜下层含有免疫细胞残余群体，这些细胞在几个月后恢复到基线水平。膀胱内灌注壳聚糖/IL-12是一种耐受性良好的有效免疫疗法，值得进一步考虑在人体中进行测试，用于治疗浅表性膀胱癌。
