Butterfield Lisa H, Comin-Anduix Begonya, Vujanovic Lazar, Lee Yohan, Dissette Vivian B, Yang Jin-Quan, Vu Hong T, Seja Elizabeth, Oseguera Denise K, Potter Douglas M, Glaspy John A, Economou James S, Ribas Antoni
Department of Medicine, University of Pittsburgh Cancer Institute, Pittsburgh, PA 15213, USA.
J Immunother. 2008 Apr;31(3):294-309. doi: 10.1097/CJI.0b013e31816a8910.
We performed a phase 1/2 trial testing the safety, toxicity, and immune response of a vaccine consisting of autologous dendritic cells (DCs) transduced with a replication-defective adenovirus (AdV) encoding the full-length melanoma antigen MART-1/Melan-A (MART-1). This vaccine was designed to activate MART-1-specific CD+8 and CD4+ T cells. Metastatic melanoma patients received 3 injections of 10(6) or 10(7) DCs, delivered intradermally. Cell surface phenotype and cytokine production of the DCs used for the vaccines were tested, and indicated intermediate maturity. CD8+ T-cell responses to MART-1 27-35 were assessed by both major histocompatibility complex class I tetramer and interferon (IFN)-gamma enzyme-linked immunosorbent spot (ELISPOT) before, during, and after each vaccine and CD4+ T-cell responses to MART-1 51-73 were followed by IFN-gamma ELISPOT. We also measured antigen response breadth. Determinant spreading from the immunizing antigen MART-1 to other melanoma antigens [gp100, tyrosinase, human melanoma antigen-A3 (MAGE-A3)] was assessed by IFN-gamma ELISPOT. Twenty-three patients were enrolled and 14 patients received all 3 scheduled DC vaccines. Significant CD8+ and/or CD4+ MART-1-specific T-cell responses were observed in 6/11 and 2/4 patients evaluated, respectively, indicating that the E1-deleted adenovirus encoding the cDNA for MART-1/Melan-A (AdVMART1)/DC vaccine activated both helper and killer T cells in vivo. Responses in CD8+ and CD4+ T cells to additional antigens were noted in 2 patients. The AdVMART1-transduced DC vaccine was safe and immunogenic in patients with metastatic melanoma.
我们开展了一项1/2期试验，测试一种由用编码全长黑色素瘤抗原MART-1/Melan-A（MART-1）的复制缺陷型腺病毒（AdV）转导的自体树突状细胞（DC）组成的疫苗的安全性、毒性和免疫反应。该疫苗旨在激活MART-1特异性CD8⁺和CD4⁺ T细胞。转移性黑色素瘤患者接受3次皮内注射10⁶或10⁷个DC。对用于疫苗的DC的细胞表面表型和细胞因子产生进行了检测，结果表明其为中等成熟度。在每次疫苗接种前、接种期间和接种后，通过主要组织相容性复合体I类四聚体和干扰素（IFN）-γ酶联免疫斑点法（ELISPOT）评估CD8⁺ T细胞对MART-1 27-35的反应，通过IFN-γ ELISPOT追踪CD4⁺ T细胞对MART-1 51-73的反应。我们还测量了抗原反应广度。通过IFN-γ ELISPOT评估从免疫抗原MART-1到其他黑色素瘤抗原[gp100、酪氨酸酶、人类黑色素瘤抗原A3（MAGE-A3）]的决定簇扩展。招募了23名患者，14名患者接受了全部3剂预定的DC疫苗。分别在6/11和2/4例接受评估的患者中观察到显著的CD8⁺和/或CD4⁺ MART-1特异性T细胞反应，表明编码MART-1/Melan-A cDNA的E1缺失腺病毒（AdVMART1）/DC疫苗在体内激活了辅助性和杀伤性T细胞。在2例患者中观察到CD8⁺和CD4⁺ T细胞对其他抗原的反应。AdVMART1转导的DC疫苗在转移性黑色素瘤患者中是安全且具有免疫原性的。
