Arlen Philip M, Gulley James L, Parker Catherine, Skarupa Lisa, Pazdur Mary, Panicali Dennis, Beetham Patricia, Tsang Kwong Y, Grosenbach Douglas W, Feldman Jarett, Steinberg Seth M, Jones Elizabeth, Chen Clara, Marte Jennifer, Schlom Jeffrey, Dahut William
Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892-1750, USA.
Clin Cancer Res. 2006 Feb 15;12(4):1260-9. doi: 10.1158/1078-0432.CCR-05-2059.
Docetaxel has activity against androgen-independent prostate cancer and preclinical studies have shown that taxane-based chemotherapy can enhance antitumor response of vaccines. The primary objective of this study was to determine if concurrent docetaxel (with dexamethasone) had any effect on generating an immune response to the vaccine. Secondary end points were whether vaccine could be given safely with docetaxel and the clinical outcome of the treatment regimen.
The vaccination regimen was composed of (a) recombinant vaccinia virus (rV) that expresses the prostate-specific antigen gene (rV-PSA) admixed with (b) rV that expresses the B7.1 costimulatory gene (rV-B7.1), and (c) sequential booster vaccinations with recombinant fowlpox virus (rF-) containing the PSA gene (rF-PSA). Patients received granulocyte macrophage colony-stimulating factor with each vaccination. Twenty-eight patients with metastatic androgen-independent prostate cancer were randomized to receive either vaccine and weekly docetaxel or vaccine alone. Patients on the vaccine alone arm were allowed to cross over to receive docetaxel alone at time of disease progression. The ELISPOT assay was used to monitor immune responses for PSA-specific T cells.
The median increase in these T-cell precursors to PSA was 3.33-fold in both arms following 3 months of therapy. In addition, immune responses to other prostate cancer-associated tumor antigens were also detected postvaccination. Eleven patients who progressed on vaccine alone crossed over to receive docetaxel at time of progression. Median progression-free survival on docetaxel was 6.1 months after receiving vaccine compared with 3.7 months with the same regimen in a historical control.
This is the first clinical trial to show that docetaxel can be administered safely with immunotherapy without inhibiting vaccine specific T-cell responses. Furthermore, patients previously vaccinated with an anticancer vaccine may respond longer to docetaxel compared with a historical control of patients receiving docetaxel alone. Larger prospective clinical studies will be required to validate these findings.
多西他赛对雄激素非依赖性前列腺癌具有活性，临床前研究表明基于紫杉烷的化疗可增强疫苗的抗肿瘤反应。本研究的主要目的是确定多西他赛（联合地塞米松）同时使用是否对疫苗产生免疫反应有任何影响。次要终点是疫苗与多西他赛联合使用是否安全以及治疗方案的临床结果。
疫苗接种方案由（a）表达前列腺特异性抗原基因的重组痘苗病毒（rV-PSA）与（b）表达B7.1共刺激基因的rV（rV-B7.1）混合组成，以及（c）用含PSA基因的重组鸡痘病毒（rF-PSA）进行序贯加强接种。每次接种时患者接受粒细胞巨噬细胞集落刺激因子。28例转移性雄激素非依赖性前列腺癌患者被随机分为接受疫苗联合每周一次多西他赛治疗或仅接受疫苗治疗。仅接受疫苗治疗组的患者在疾病进展时可交叉接受单纯多西他赛治疗。采用ELISPOT试验监测针对PSA特异性T细胞的免疫反应。
治疗3个月后，两组中这些针对PSA的T细胞前体的中位数增加均为3.33倍。此外，接种疫苗后还检测到对其他前列腺癌相关肿瘤抗原的免疫反应。11例仅接受疫苗治疗后病情进展的患者在进展时交叉接受多西他赛治疗。接受疫苗后接受多西他赛治疗的患者的无进展生存期中位数为6.1个月，而历史对照中相同方案的无进展生存期为3.7个月。
这是第一项表明多西他赛可与免疫疗法安全联合使用且不抑制疫苗特异性T细胞反应的临床试验。此外，与仅接受多西他赛治疗的历史对照患者相比，先前接种过抗癌疫苗的患者对多西他赛的反应可能更长。需要更大规模的前瞻性临床研究来验证这些发现。
