Mehrotra Shikhar, Britten Carolyn D, Chin Steve, Garrett-Mayer Elizabeth, Cloud Colleen A, Li Mingli, Scurti Gina, Salem Mohamed L, Nelson Michelle H, Thomas Melanie B, Paulos Chrystal M, Salazar Andres M, Nishimura Michael I, Rubinstein Mark P, Li Zihai, Cole David J
Department of Surgery, Medical University of South Carolina, 96 Jonathan Lucas Street, Charleston, SC, 29425, USA.
Department of Microbiology and Immunology, Medical University of South Carolina, Charleston, SC, 29425, USA.
J Hematol Oncol. 2017 Apr 7;10(1):82. doi: 10.1186/s13045-017-0459-2.
Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC).
We generated autologous DCs from the peripheral blood of HLA-A2 patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 10 peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 μg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells.
Twelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I -tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease.
Vaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC.
NCT01410968 ; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).
树突状细胞（DCs）可提高癌症患者抗肿瘤免疫反应的质量。因此，我们认为基于DC的免疫疗法联合Toll样受体（TLR）-3激动剂聚肌胞苷酸-聚左旋赖氨酸-羧甲基纤维素（poly-ICLC）是一种有前景的方法，可用于激发针对转移性或局部晚期不可切除胰腺癌（PC）的免疫反应。
我们从HLA-A2型PC患者的外周血中生成自体DC。DC用三种不同的A2限制性肽进行脉冲处理：1）人端粒酶逆转录酶（hTERT，TERT572Y），2）癌胚抗原（CEA；Cap1-6D），以及3）生存素（SRV.A2）。患者每2周接受4次皮内注射1×10个肽脉冲DC疫苗（第0、14、28和42天）。同时，患者在接种日（即第0、14、28和42天）以及第3、17、21、31、37和45天接受30μg/Kg的聚肌胞苷酸-聚左旋赖氨酸-羧甲基纤维素肌肉注射。我们的主要目标是评估安全性和可行性。在每次DC注射时间点，通过枚举患者T细胞的表型和功能来测量DC疫苗接种对免疫反应的影响。
12例患者接受了血液成分单采：9例转移性疾病患者和3例局部晚期不可切除疾病患者。所有个体的疫苗均成功制备。我们发现这种治疗耐受性良好，最常见的症状是疲劳和/或自限性流感样症状。在第56天接受成像检查的8例患者中，4例病情稳定，4例病情进展。中位总生存期为7.7个月。1例患者在白细胞分离术后存活了28个月。疫苗接种前后的MHC I类四聚体分析显示，3例病情稳定的患者有效产生了抗原特异性T细胞。
肽脉冲DC联合聚肌胞苷酸-聚左旋赖氨酸-羧甲基纤维素进行疫苗接种是安全的，并能在晚期PC患者中诱导出可测量的肿瘤特异性T细胞群体。
NCT01410968；注册机构名称：clinicaltrials.gov；注册日期：2011年4月8日）
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