Intravesical chitosan/interleukin-12 immunotherapy induces tumor-specific systemic immunity against murine bladder cancer.
Intravesical chitosan/interleukin-12 immunotherapy induces tumor-specific systemic immunity against murine bladder cancer.
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膀胱内壳聚糖/白细胞介素 12 免疫疗法可诱导针对小鼠膀胱癌的肿瘤特异性全身免疫。
DOI：
10.1007/s00262-015-1672-x
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Zaharoff,DavidA
中科院分区：
文献类型：
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作者：
Smith,SeanG;Koppolu,BhanuPrasanth;Ravindranathan,Sruthi;Kurtz,SamanthaL;Yang,Lirong;Katz,MatthewD;Zaharoff,DavidA
膀胱癌是一种高度复发的疾病，需要新的，持久的治疗策略。本研究评估了由生物聚合物壳聚糖与白细胞介素-12（CS/IL-12）的共制剂组成的膀胱内免疫疗法诱导全身适应性肿瘤特异性免疫的能力。膀胱内CS/IL-12免疫疗法用于治疗已建立的原位MB 49和MBT-2膀胱肿瘤。所有接受膀胱内CS/IL-12免疫疗法的小鼠均经历了原位疾病的高治愈率。为了研究所产生的适应性免疫应答的持久性和程度，对治愈的小鼠进行局部（膀胱内）和远端再激发。治愈的小鼠以肿瘤特异性方式拒绝100%的膀胱内肿瘤再激发和50- 100%的远端皮下再激发。在体外评估来自治愈小鼠的脾细胞以肿瘤特异性方式裂解靶标的能力，揭示来自治愈小鼠的脾细胞的裂解活性是稳健的和肿瘤特异性的。保护性免疫是持久的，在免疫治疗后至少持续18个月。在晚期膀胱癌模型中，膀胱内CS/IL-12免疫治疗控制了70%治疗小鼠的原位和皮下肿瘤。膀胱内CS/IL-12免疫疗法产生针对膀胱癌的稳健且持久的肿瘤特异性适应性免疫应答。该疗法治疗浅表和晚期疾病的特异性、持久性和潜力值得考虑用于临床转化。
Bladder cancer is a highly recurrent disease in need of novel, durable treatment strategies. This study assessed the ability of an intravesical immunotherapy composed of a coformulation of the biopolymer chitosan with interleukin-12 (CS/IL-12) to induce systemic adaptive tumor-specific immunity. Intravesical CS/IL-12 immunotherapy was used to treat established orthotopic MB49 and MBT-2 bladder tumors. All mice receiving intravesical CS/IL-12 immunotherapy experienced high cure rates of orthotopic disease. To investigate the durability and extent of the resultant adaptive immune response, cured mice were rechallenged both locally (intravesically) and distally. Cured mice rejected 100 % of intravesical tumor rechallenges and 50–100 % of distant subcutaneous rechallenges in a tumor-specific manner. The ability of splenocytes from cured mice to lyse targets in a tumor-specific manner was assessed in vitro, revealing that lytic activity of splenocytes from cured mice was robust and tumor specific. Protective immunity was durable, lasting for at least 18 months after immunotherapy. In an advanced bladder cancer model, intravesical CS/IL-12 immunotherapy controlled simultaneous orthotopic and subcutaneous tumors in 70 % of treated mice. Intravesical CS/IL-12 immunotherapy creates a robust and durable tumor-specific adaptive immune response against bladder cancer. The specificity, durability, and potential of this therapy to treat both superficial and advanced disease are deserving of consideration for clinical translation.