Abstract

BACKGROUND:

New bladder preserving strategies are needed for muscle invasive bladder cancer (MIBC). Combined therapy of immune-checkpoint inhibitors and radiation was shown to have synergistic antitumoral effects in preclinical studies.

OBJECTIVES:

We aim to evaluate whether the sequence of administration of this combined therapy impacts antitumoral response.

METHODS:

We developed an in-vivo syngeneic MIBC mouse model where murine bladder cancer cells (MB49) were injected subcutaneously in the right flank of C57BL/6 mice. Mice were then randomized to the following treatments: control, anti-programmed cell death ligand 1 (PD-L1) alone, radiation alone (XRT) consisting of 6.25 Gy x2 fractions, concurrent anti-PD-L1 with XRT, neoadjuvant anti-PD-L1 followed by XRT, or XRT followed by adjuvant anti-PD-L1 therapy. Tumor growth, survival, and rate of response were analyzed.

RESULTS:

Total of 60 mice were randomized. One-way analysis of variance showed statistically significant difference in tumor growth rate across the treatment arms (p = 0.029). Importantly, timing of immunotherapy (neoadjuvant, concurrent, or adjuvant) did not alter either tumor growth or survival (p > 0.05). The rate of response was also similar in each combination arm (p > 0.05).

CONCLUSION:

Combining anti-PD-L1 immunotherapy and radiation therapy offers optimal antitumoral responses. Timing of immunotherapy (neoadjuvant, concurrent, or adjuvant) does not appear to affect outcomes. Whether the toxicity profile differs across various sequential deliveries of combination therapy requires further evaluation.

中文翻译：

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PD-L1免疫检查点抑制剂的序列优化和放射疗法在膀胱癌中的应用

摘要

背景：

肌肉浸润性膀胱癌（MIBC）需要新的膀胱保存策略。临床前研究表明，免疫检查点抑制剂和放射疗法的联合治疗具有协同抗肿瘤作用。

目标：

我们旨在评估这种联合疗法的给药顺序是否会影响抗肿瘤反应。

方法：

我们开发了一种体内同基因MIBC小鼠模型，其中将鼠膀胱癌细胞（MB49）皮下注射到C57BL / 6小鼠的右侧腹中。然后将小鼠随机接受以下治疗：对照，单独的抗程序性细胞死亡配体1（PD-L1），由6.25 Gy x2组分组成的单独放射线（XRT），同时具有XRT的抗PD-L1，新辅助抗PD -L1继之以XRT，或XRT继之以辅助性抗PD-L1治疗。分析了肿瘤的生长，存活率和反应率。

结果：

总共60只小鼠被随机分组​​。单向方差分析显示各治疗组的肿瘤生长率在统计学上有显着差异（p  = 0.029）。重要的是，免疫治疗的时机（新辅助，同时或辅助）既不会改变肿瘤的生长，也不会改变生存率（p  > 0.05）。每个组合组的反应率也相似（p  > 0.05）。

结论：

抗PD-L1免疫疗法和放射疗法的结合可提供最佳的抗肿瘤反应。免疫治疗的时间（新辅助，并行或辅助）似乎不会影响预后。联合治疗的各种顺序给药中毒性谱是否有所不同，需要进一步评估。