ASCO GI 2014：两种胰腺癌疫苗序贯应用对晚期胰腺癌疗效良好

晚期胰腺癌的预后极差。已报道的最佳的11个月中位生存期来自一线化疗方案FOLFIRINOX 。但是，由于其副作用，只有最适合的患者才能治疗，且其它化疗方案报告的存活率较低。对已用一线治疗但疾病仍进展的患者来说，二线治疗的中位生存期从4-6个月不等，三线治疗则为2-4个月。

在2014 ASCO GI会议上，研究家们公布一项转移性胰腺导管腺癌（PDAC）患者随机II期研究新结果，数据表明与单用GVAX治疗相比，两种不同的抗肿瘤疫苗治疗（先GVAX序贯CRS-207）可提高生存期。接受至少两剂GVAX以及至少一剂CRS-207的患者以及既往接受两种及以上治疗方案患者的差异最大。

来自约翰霍普金斯大学悉尼金梅尔综合癌症中心的研究第一作者Dung T. Le教授说：“这是首个显示免疫治疗对胰腺癌有效的随机化研究。这项研究仅仅是第一步，我们相信我们将能够进一步的应用这种方法。我们使用了各种化疗药物，但尚无二线或三线治疗的标准治疗方案。我们很高兴这些患者可能很快就会有副作用较少的化疗替代方案。”

本研究检测了一种新型免疫治疗策略，该策略有望改善此类患者的预后，且耐受性似乎比化疗好。GVAX疫苗由已进行遗传修饰可分泌一种称为GM-CSF蛋白（这种蛋白可刺激免疫系统）的胰腺癌细胞构成。该疫苗与低剂量常见癌症药物环磷酰胺联用可增强疫苗疗效。第二种疫苗，CRS-207，是一种李斯特菌，已经遗传修饰可供人安全使用，同时保留其刺激免疫系统的能力。具体而言，CRS-207已被改造以刺激产生间皮素蛋白免疫应答，而胰腺癌细胞中存在高水平皮素蛋白。

两种疫苗联用可刺激产生胰抗腺肿瘤细胞免疫应答，GVAX先诱导抗多种肿瘤蛋白的广泛应答，之后CRS-207刺激产生抗间皮素蛋白免疫应答。从本质上讲，这种疫苗联合接种法可增强患者的天然免疫系统，并使其识别和攻击胰腺肿瘤。

90例转移性PDAC（最常见的胰腺癌类型）患者中被纳入研究，并随机分配GVAX治疗序贯CRS -207治疗（A组）或单独GVAX治疗（B组）。几乎所有的患者既往都曾接受过至少一种化疗。计划中的一项中期分析显示，两联疫苗疗法的中位总生存期明显较单独GVAX 长（6.1个月 VS 3.9个月）。一年后，A组约24％的患者仍存活，B组为12％。

接受至少三剂疫苗的患者中（占所有患者的70％），A组接受2剂GVAX以及至少一剂CRS-207的患者的中位总生存期为9.7个月，与之相比，单独GVAX治疗患者的中位总生存期为4.6个月。根据本中期分析中观察到的疗效，患者允许从B组转到A组。该疫苗的副作用相对较轻，可很快缓解，每次治疗剂量下并未加重（化疗则较常出现）。

GVAX/CRS-207联用是根据临床调查制定的几种相关免疫治疗策略之一。研究人员将要进行一项大型II期研究，将对这种疫苗组合与CRS -207及单独化疗作为转移性胰腺癌的二线治疗或主要治疗进行比较。他们也在研究GVAX/CRS-207与免疫关键点抑制剂如ipilimumab及anti-PD-1/PD-L1的联用。最近已进行了一项检测GVAX /ipilimumab的研究，研究中GVAX/ipilimumab作为FOLFIRINOX方案治疗后病情稳定患者的维持治疗。

ASCO 2014 Gastrointestinal Cancer Symposium: Abstract 177.

Background:
Immunotherapy for pancreatic ductal adenocarcinoma (PDA) is likely to require synergistic combinations. One approach is to use heterologous prime boost vaccinations to capitalize on immunostimulatory features of distinct vectors. GVAX is irradiated, GM-CSF-secreting allogeneic pancreatic cell lines given intradermally to elicit a broad antigenic response. Low-dose cyclophosphamide (CY) is given prior to GVAX to inhibit regulatory T-cells. CRS-207 is live-attenuated Listeria monocytogenes (Lm) which expresses mesothelin and stimulates innate and adaptive immunity. In mouse tumor models, Lm/GVAX vaccines are synergistic and in the Phase 1 study of CRS-207, 3 PDA patients who had received prior GVAX lived ≥15 months (mos).

Methods:
Metastatic PDA patients (ECOG 0-1; adequate organ function) who received or refused ≥1 prior chemotherapy were randomized 2:1 to receive either 2 doses of CY/GVAX followed by 4 doses of CRS-207 (Arm A) or 6 doses of CY/GVAX (Arm B) every 3 weeks. Courses could be repeated. The primary endpoint was to compare overall survival (OS) between the arms. Secondary endpoints were safety, clinical and immune responses. One-sided p-values are reported. 

Results:
90 patients (Full Analysis Set [FAS]; A: 61, B: 29), of which 51% had received ≥2 chemotherapy regimens for metastatic PDA, were treated. After a median  follow-up of 7.8 mos, median OS in FAS was 6.1 vs 3.9 mos (A vs B; HR=0.54, p=0.011). Median OS in patients who received ≥3 doses (per protocol [PP] set: 2 doses of CY/GVAX and ≥1 dose of CRS-207 in A or ≥3 doses of CY/GVAX in B) was 9.7 vs 4.6 mos (A vs B; HR=0.44, p=0.0074). The treatment effect was particularly evident in patients who received ≥2 prior regimens for metastatic PDA with median OS of 5.1 vs 3.7 mos (A vs B; HR=0.34, p=0.001). OS in the PP set was 8.2 vs 4.0 mos (A vs B; HR=0.23, p=0.0003). CA19-9 stabilization was seen in 32% vs 13% of patients (A vs B; p=0.06). Toxicities included local reactions after GVAX and transient fevers, rigors and lymphopenia after CRS-207.

Conclusions:
CY/GVAX followed by CRS-207 shows extended survival with manageable toxicity in previously-treated metastatic PDA and warrants further study.

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Lee MG, Lee SH, Lee SJ, Lee YS, Hwang JH, Ryu JK, Kim YT, Kim DU, Woo SM.5-Fluorouracil/Leucovorin Combined with Irinotecan and Oxaliplatin (FOLFIRINOX) as Second-Line Chemotherapy in Patients with Advanced Pancreatic Cancer Who Have Progressed on Gemcitabine-Based Therapy.Chemotherapy. 2014 Jan 18;59(4):273-279