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A phase 2 study of GVAX colon vaccine with cyclophosphamide and pembrolizumab in patients with mismatch repair proficient advanced colorectal cancer.
Cancer Medicine ( IF 2.9 ) Pub Date : 2019-12-26 , DOI: 10.1002/cam4.2763 Mark Yarchoan 1 , Chiung-Yu Huang 1 , Qingfeng Zhu 1 , Anna K Ferguson 1 , Jennifer N Durham 1 , Robert A Anders 1 , Elizabeth D Thompson 1 , Noah S Rozich 1 , Dwayne L Thomas 1 , Julie M Nauroth 1 , Christina Rodriguez 1 , Arsen Osipov 1 , Ana De Jesus-Acosta 1 , Dung T Le 1 , Adrian G Murphy 1 , Daniel Laheru 1 , Ross C Donehower 1 , Elizabeth M Jaffee 1 , Lei Zheng 1 , Nilofer S Azad 1
Cancer Medicine ( IF 2.9 ) Pub Date : 2019-12-26 , DOI: 10.1002/cam4.2763 Mark Yarchoan 1 , Chiung-Yu Huang 1 , Qingfeng Zhu 1 , Anna K Ferguson 1 , Jennifer N Durham 1 , Robert A Anders 1 , Elizabeth D Thompson 1 , Noah S Rozich 1 , Dwayne L Thomas 1 , Julie M Nauroth 1 , Christina Rodriguez 1 , Arsen Osipov 1 , Ana De Jesus-Acosta 1 , Dung T Le 1 , Adrian G Murphy 1 , Daniel Laheru 1 , Ross C Donehower 1 , Elizabeth M Jaffee 1 , Lei Zheng 1 , Nilofer S Azad 1
Affiliation
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BACKGROUND
Mismatch repair proficient (MMRp) colorectal cancer (CRC) has been refractory to single-agent programmed cell death protein 1 (PD1) inhibitor therapy. Colon GVAX is an allogeneic, whole-cell, granulocyte-macrophage colony-stimulating factor -secreting cellular immunotherapy that induces T-cell immunity against tumor-associated antigens and has previously been studied in combination with low-dose cyclophosphamide (Cy) to inhibit regulatory T cells.
METHODS
We conducted a single-arm study of GVAX/Cy in combination with the PD1 inhibitor pembrolizumab in patients with advanced MMRp CRC. Patients received pembrolizumab plus Cy on day 1, GVAX on day 2, of a 21-day cycle. The primary endpoint was the objective response rate by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Secondary objectives included safety, overall survival, progression-free survival, changes in carcinoembryonic antigen (CEA) levels, and immune-related correlates.
RESULTS
Seventeen patients were enrolled. There were no objective responses, and the disease control rate was 18% by RECIST 1.1. The median progression-free survival was 82 days (95% confidence interval [CI], 48-97 days) and the median overall survival was 213 days (95% CI 179-441 days). Biochemical responses (≥30% decline in CEA) were observed in 7/17 (41%) of patients. Grade ≥ 3 treatment-related adverse events were observed in two patients (hemolytic anemia and corneal transplant rejection). Paired pre- and on-treatment biopsy specimens showed increases in programmed death-ligand 1 expression and tumor necrosis in a subset of patients.
CONCLUSIONS
GVAX/Cy plus pembrolizumab failed to meet its primary objective in MMRp CRC. Biochemical responses were observed in a subset of patients and have not previously been observed with pembrolizumab monotherapy in MMRp CRC, indicating that GVAX may modulate the antitumor immune response.
中文翻译：
GVAX结肠疫苗与环磷酰胺和pembrolizumab的2期研究用于错配修复熟练的晚期大肠癌患者。
背景技术错配修复熟练（MMRp）结直肠癌（CRC）对于单药程序性细胞死亡蛋白1（PD1）抑制剂治疗是难治的。结肠GVAX是一种同种异体，全细胞，粒细胞巨噬细胞集落刺激因子分泌细胞免疫疗法，可诱导针对肿瘤相关抗原的T细胞免疫，并且先前已与低剂量环磷酰胺（Cy）结合进行研究以抑制调节性T细胞。方法我们对晚期MMRp CRC患者进行了GVAX / Cy与PD1抑制剂pembrolizumab联合单臂研究。在21天周期的第1天，患者接受pembrolizumab联合Cy的治疗，并在第2天接受GVAX。主要终点是根据实体肿瘤缓解评估标准（RECIST）1.1版的客观缓解率。次要目标包括安全性，总体生存率，无进展生存期，癌胚抗原（CEA）水平变化以及与免疫相关的相关因素。结果招募了17名患者。没有客观反应，RECIST 1.1的疾病控制率为18％。中位无进展生存期为82天（95％置信区间[CI]为48-97天），中位总生存期为213天（95％CI 179-441天）。在7/17（41％）的患者中观察到生化反应（CEA下降≥30％）。在两名患者中观察到≥3级与治疗相关的不良事件（溶血性贫血和角膜移植排斥）。配对的治疗前和治疗中活检标本显示部分患者中程序性死亡配体1表达和肿瘤坏死增加。结论GVAX / Cy加pembrolizumab未能达到其MMRp CRC的主要目标。在亚类患者中观察到了生化反应，而以前在MMRp CRC中未使用派姆单抗单药治疗时未观察到生化反应，这表明GVAX可能会调节抗肿瘤免疫反应。
更新日期：2019-12-27
中文翻译：
GVAX结肠疫苗与环磷酰胺和pembrolizumab的2期研究用于错配修复熟练的晚期大肠癌患者。
背景技术错配修复熟练（MMRp）结直肠癌（CRC）对于单药程序性细胞死亡蛋白1（PD1）抑制剂治疗是难治的。结肠GVAX是一种同种异体，全细胞，粒细胞巨噬细胞集落刺激因子分泌细胞免疫疗法，可诱导针对肿瘤相关抗原的T细胞免疫，并且先前已与低剂量环磷酰胺（Cy）结合进行研究以抑制调节性T细胞。方法我们对晚期MMRp CRC患者进行了GVAX / Cy与PD1抑制剂pembrolizumab联合单臂研究。在21天周期的第1天，患者接受pembrolizumab联合Cy的治疗，并在第2天接受GVAX。主要终点是根据实体肿瘤缓解评估标准（RECIST）1.1版的客观缓解率。次要目标包括安全性，总体生存率，无进展生存期，癌胚抗原（CEA）水平变化以及与免疫相关的相关因素。结果招募了17名患者。没有客观反应，RECIST 1.1的疾病控制率为18％。中位无进展生存期为82天（95％置信区间[CI]为48-97天），中位总生存期为213天（95％CI 179-441天）。在7/17（41％）的患者中观察到生化反应（CEA下降≥30％）。在两名患者中观察到≥3级与治疗相关的不良事件（溶血性贫血和角膜移植排斥）。配对的治疗前和治疗中活检标本显示部分患者中程序性死亡配体1表达和肿瘤坏死增加。结论GVAX / Cy加pembrolizumab未能达到其MMRp CRC的主要目标。在亚类患者中观察到了生化反应，而以前在MMRp CRC中未使用派姆单抗单药治疗时未观察到生化反应，这表明GVAX可能会调节抗肿瘤免疫反应。
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