Keedy Vicki, Wang Wei, Schiller Joan, Chada Sunil, Slovis Bonnie, Coffee Keith, Worrell John, Thet Lyn A, Johnson David H, Carbone David P
Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA.
J Clin Oncol. 2008 Sep 1;26(25):4166-71. doi: 10.1200/JCO.2007.15.6927.
This pilot phase I trial evaluated the safety and maximum-tolerated dose of p53 gene transfer using an adenovirus vector (Ad-p53) delivered via bronchoalveolar lavage (BAL) to patients with bronchioloalveolar lung carcinoma (BAC).
Patients were initially administered two treatments of Ad-p53 to a single involved lobe, beginning at 2 x 10(9) viral particles (vp) per dose and escalated to a maximum of 2 x 10(12) vp. If a clinical benefit was seen and the treatment was well tolerated, additional doses could be administered to additional lobes.
Twenty-five patients were treated at doses between 2 x 10(9) and 2 x 10(12) vp. At 2 x 10(12) vp, one patient experienced grade 4 pulmonary toxicity, and one patient died 25 days after his second cycle; therefore, a cohort of 10 patients was treated at the recommended phase II dose of 5 x 10(11) vp, with no grade 4 toxicity observed. The most frequent toxicities included low-grade fever, hypoxia, and dyspnea. Of the 23 assessable patients, 16 had stable disease as their best response. Subjective improvement in breathing was noted in eight patients. Limited distribution of vector was observed, with transient detection in patient sputum for 1 to 2 days after administration.
Ad-p53 can be administered safely by BAL at 5 x 10(11) vp with repeated dosing. Stabilization of disease and symptomatic improvement may warrant further studies of Ad-p53 or other adenoviruses administered by BAL in patients with BAC.
本I期试验性研究评估了通过支气管肺泡灌洗（BAL）将携带p53基因的腺病毒载体（Ad-p53）递送至细支气管肺泡癌（BAC）患者体内的安全性及最大耐受剂量。
患者最初接受两次向单个受累肺叶给予Ad-p53的治疗，起始剂量为每剂2×10⁹病毒颗粒（vp），并逐步增加至最大剂量2×10¹² vp。如果观察到临床获益且治疗耐受性良好，则可向其他肺叶给予额外剂量。
25例患者接受了剂量在2×10⁹至2×10¹² vp之间的治疗。在2×10¹² vp剂量时，1例患者出现4级肺部毒性，1例患者在第二个周期后25天死亡；因此，10例患者按照推荐的II期剂量5×10¹¹ vp进行治疗，未观察到4级毒性。最常见的毒性包括低热、低氧血症和呼吸困难。在23例可评估的患者中，16例患者的最佳反应为疾病稳定。8例患者呼吸有主观改善。观察到载体分布有限，给药后1至2天在患者痰液中短暂检测到。
通过BAL以5×10¹¹ vp的剂量重复给药Ad-p53是安全的。疾病稳定和症状改善可能值得进一步研究通过BAL给予Ad-p53或其他腺病毒用于BAC患者。
