Department of Radiation Oncology, Vanderbilt University Medical Center, Nashville, Tennessee.
Vanderbilt University School of Medicine, Nashville, Tennessee.
J Urol. 2021 May;205(5):1336-1343. doi: 10.1097/JU.0000000000001576. Epub 2020 Dec 24.
Nonmuscle-invasive bladder cancer is treated by resection within the bladder and bladder instillment with bacillus Calmette-Guérin or chemotherapy. For bacillus Calmette-Guérin-refractory disease, systemic anti-PD-1 (programmed cell death protein 1) immune checkpoint inhibition is a treatment. Our aim is to test whether intravesical instillment with anti-PD-1 inhibitor treats localized bladder cancer as effectively as systemic administration.
We investigated an orthotopic mouse model of urothelial bladder cancer using MBT2 cells instilled into the bladders of syngeneic, wild-type C3H mice. Groups of 10 mice received each treatment for comparison of intravesical anti-PD-1, intraperitoneal anti-PD1, and intravesical chemotherapy. The primary outcome was overall survival and secondary outcomes included long-term immunity and toxicity.
Anti-PD-1 administered by bladder instillment (intravesical route) successfully treats localized bladder cancer and has similar overall survival to anti-PD-1 by systemic route. Anti-PD-1 by either route provides a significant survival advantage over control antibody. Anti-PD-1 increases CD8+ cell infiltration in tumors, particularly when administered intravesically. Antibody treatment avoids toxicity observed for intravesical chemotherapy. Mice who cleared their tumors after initial treatment were rechallenged with tumor engraftment 3-9 months later without any additional treatment. Initial anti-PD-1-treated mice did not grow tumors when rechallenged, which suggests long-term immunity exists, but initial mitomycin-treated mice readily grew tumors indicating no immunity occurred by chemotherapy treatment.
Intravesical administration of anti-PD-1 is a promising treatment route for localized bladder cancer, with comparable overall survival to systemic anti-PD-1 in this mouse model. Intravesical anti-PD-1 increases CD8+ T cells in treated tumors and long-term immunity was seen to tumor rechallenge.
非肌肉浸润性膀胱癌通过在膀胱内切除并膀胱内灌注卡介苗或化疗进行治疗。对于卡介苗耐药疾病，全身抗 PD-1（程序性细胞死亡蛋白 1）免疫检查点抑制是一种治疗方法。我们的目的是测试膀胱内灌注抗 PD-1 抑制剂是否与全身给药一样有效地治疗局部膀胱癌。
我们使用 MBT2 细胞在同基因、野生型 C3H 小鼠的膀胱中灌注，研究了尿路上皮膀胱癌的原位小鼠模型。为了比较膀胱内抗 PD-1、腹腔内抗 PD-1 和膀胱内化疗，每组 10 只小鼠接受每种治疗。主要结局是总生存期，次要结局包括长期免疫和毒性。
膀胱内灌注（膀胱途径）给予抗 PD-1 成功治疗局部膀胱癌，与全身途径给予抗 PD-1 的总生存期相似。通过任何途径给予抗 PD-1 均比对照抗体提供显著的生存优势。抗 PD-1 增加了肿瘤内 CD8+细胞浸润，特别是当膀胱内给药时。抗体治疗避免了膀胱内化疗观察到的毒性。最初治疗后清除肿瘤的小鼠在 3-9 个月后再次用肿瘤移植进行再挑战，而无需任何额外的治疗。最初接受抗 PD-1 治疗的小鼠在再次挑战时未生长肿瘤，这表明存在长期免疫，但最初接受丝裂霉素治疗的小鼠容易生长肿瘤，表明化疗治疗未产生免疫。
膀胱内给予抗 PD-1 是局部膀胱癌的一种有前途的治疗途径，在这种小鼠模型中与全身抗 PD-1 的总生存期相当。膀胱内抗 PD-1 增加了治疗肿瘤中的 CD8+T 细胞，并观察到对肿瘤再挑战的长期免疫。
