Rosenberg Steven A, Yang James C, Schwartzentruber Douglas J, Hwu Patrick, Topalian Suzanne L, Sherry Richard M, Restifo Nicholas P, Wunderlich John R, Seipp Claudia A, Rogers-Freezer Linda, Morton Kathleen E, Mavroukakis Sharon A, Gritz Linda, Panicali Dennis L, White Donald E
Center for Cancer Research, Surgery Branch, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Clin Cancer Res. 2003 Aug 1;9(8):2973-80.
The purpose of this study was to evaluate the immunological responses and therapeutic effectiveness of immunization with fowlpox vaccines encoding the gp100 melanoma antigen in patients with metastatic melanoma.
In three consecutive clinical trials, patients were immunized with recombinant fowlpox viruses encoding three different forms of the melanoma/melanocyte-associated antigen gp100: (a) the native, full-length gp100 molecule; (b) the gp100 molecule with two amino acids modified to increase binding to HLA-A*0201 molecules; and (c) a "minigene" construct encoding a single, modified epitope gp100:209-217(210M) targeted to the endoplasmic reticulum. The immunogenicity of these constructs was studied using peripheral blood mononuclear cells to measure epitope-specific release of IFN-gamma.
Reactivity against gp100 was not seen in any patient before receiving fowlpox immunization. Whereas just one of seven patients developed reactivity after receiving fowlpox encoding native gp100, 10 of 14 patients who received fowlpox encoding the anchor modified full-length gp100 exhibited reactivity against the native gp100 molecule, and 12 of 16 patients were successfully immunized after inoculation with the modified minigene construct (p2 = 0.02). There was no difference in the latter group between those randomized to vaccination by i.v. or i.m. routes. There was one partial cancer regression in the group of 46 patients receiving virus in the absence of interleukin (IL)-2. Once patients showed evidence of progressive disease, they were eligible for "cross-over" treatment to IL-2 alone or with the fowlpox virus. None of the 13 patients receiving the full-length or modified full-length forms of gp100 responded when receiving IL-2, whereas 6 of 12 patients who received the fowlpox containing the minigene construct and then received IL-2 showed objective cancer regressions, including three patients with complete regression.
These data underscore the importance of modifying anchor residues of nonmutated self-antigen peptides to generate cellular immune responses after immunization and support the further investigation of recombinant fowlpox viruses encoding modified epitopes administered in combination with IL-2.
本研究旨在评估用编码gp100黑色素瘤抗原的禽痘疫苗免疫转移性黑色素瘤患者的免疫反应和治疗效果。
在三项连续的临床试验中，患者用编码三种不同形式的黑色素瘤/黑色素细胞相关抗原gp100的重组禽痘病毒进行免疫：（a）天然全长gp100分子；（b）两个氨基酸经过修饰以增加与HLA - A*0201分子结合的gp100分子；（c）编码靶向内质网的单个修饰表位gp100:209 - 217(210M)的“微型基因”构建体。使用外周血单个核细胞来测量IFN - γ的表位特异性释放，研究这些构建体的免疫原性。
在接受禽痘免疫前，任何患者均未观察到针对gp100的反应性。接受编码天然gp100的禽痘疫苗后，7名患者中仅有1名产生反应性；而接受编码锚定修饰全长gp100的禽痘疫苗的14名患者中有10名表现出针对天然gp100分子的反应性；接种修饰微型基因构建体（p2 = 0.02）后，16名患者中有12名成功免疫。后一组中通过静脉或肌肉注射途径随机接种疫苗的患者之间无差异。在46名未接受白细胞介素（IL）-2的接受病毒治疗的患者组中有1例部分癌症消退。一旦患者出现疾病进展的证据，他们有资格接受单独使用IL - 2或与禽痘病毒联合的“交叉”治疗。接受全长或修饰全长形式gp100的13名患者在接受IL - 2治疗时均无反应，而接受含微型基因构建体的禽痘疫苗然后接受IL - 2治疗的12名患者中有6名出现客观的癌症消退，包括3名完全消退的患者。
这些数据强调了修饰未突变自身抗原肽的锚定残基以在免疫后产生细胞免疫反应的重要性，并支持进一步研究编码修饰表位的重组禽痘病毒与IL - 2联合给药。
