Gomes-Giacoia Evan, Miyake Makito, Goodison Steve, Sriharan Aravindhan, Zhang Ge, You Lijing, Egan Jack O, Rhode Peter R, Parker Alexander S, Chai Karl X, Wong Hing C, Rosser Charles J
Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, Florida, United States of America.
Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando, Florida, United States of America; Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida, United States of America.
PLoS One. 2014 Jun 4;9(6):e96705. doi: 10.1371/journal.pone.0096705. eCollection 2014.
Intravesical Bacillus Calmette-Guérin (BCG) has been shown to induce a specific immunologic response (i.e., activation of IL-2 and effector T-cells), while preclinical studies using ALT-803 (mutated IL-15 analogue combined with IL-15Rα-Fc fusion) have shown promising results by prolonging the agent's half-life and stimulating CD8+ T-cells. Based on these results, we hypothesized that the intravesical administration of ALT-803 along with BCG will generate an immunologic response leading to significant bladder tumor burden reduction. Using a well-established carcinogen induced rat non-muscle invasive bladder cancer (NMIBC) model, we studied the effects of intravesical ALT-803 with and without BCG. Rat tissues were evaluated to document treatment response. Intravesical ALT-803 was safe and well tolerated alone and in combination with BCG. As a single treatment agent, ALT-803 reduced tumor burden by 35% compared to control whereas BCG alone only reduced tumor burden by 15%. However, the combination of ALT-803 plus BCG reduced tumor burden by 46% compared to control. Immune monitoring suggested that the antitumor response was linked to the production and secretion of IL-1α, IL-1β and RANTES, which in turn, induced the proliferation and activation of NK cells. Lastly, tumoral responses of the combinational treatment were associated with 76% reduction in angiogenesis, which is significantly higher than when assessed with either agent alone. The enhanced therapeutic index seen with this duplet provides justification for the development of this regimen for future clinical trials.
膀胱内灌注卡介苗（BCG）已被证明可诱导特异性免疫反应（即激活白细胞介素-2和效应T细胞），而使用ALT-803（突变的白细胞介素-15类似物与白细胞介素-15Rα-Fc融合蛋白）的临床前研究通过延长该药物的半衰期和刺激CD8 + T细胞显示出了有前景的结果。基于这些结果，我们推测膀胱内给予ALT-803联合BCG将产生免疫反应，从而显著降低膀胱肿瘤负荷。我们使用成熟的致癌物诱导大鼠非肌肉浸润性膀胱癌（NMIBC）模型，研究了膀胱内给予ALT-803联合或不联合BCG的效果。对大鼠组织进行评估以记录治疗反应。膀胱内给予ALT-803单独使用以及与BCG联合使用时均安全且耐受性良好。作为单一治疗药物，与对照组相比，ALT-803使肿瘤负荷降低了35%，而单独使用BCG仅使肿瘤负荷降低了15%。然而，与对照组相比，ALT-803加BCG的联合治疗使肿瘤负荷降低了46%。免疫监测表明，抗肿瘤反应与白细胞介素-1α、白细胞介素-1β和调节激活正常T细胞表达和分泌因子（RANTES）的产生和分泌有关，进而诱导自然杀伤细胞的增殖和激活。最后，联合治疗的肿瘤反应与血管生成减少76%相关，这显著高于单独使用任何一种药物时的评估结果。这种双联疗法所显示的增强治疗指数为该方案用于未来临床试验的开发提供了依据。
