Kudo-Saito Chie, Schlom Jeffrey, Hodge James W
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute/NIH, Building 10, Bethesda, MD 93042, USA.
Clin Cancer Res. 2005 Mar 15;11(6):2416-26. doi: 10.1158/1078-0432.CCR-04-1380.
Cancer vaccines targeting tumor-associated antigens are being investigated for the therapy of tumors. Numerous strategies, including the direct intratumoral (i.t.) vaccination route, have been examined. For tumors expressing carcinoembryonic antigen (CEA) as a model tumor-associated antigen, we previously designed poxviral vectors that contain the transgenes for CEA and a triad of T-cell costimulatory molecules, B7-1, intercellular adhesion molecule-1, (ICAM-1), and leukocyte function associated antigen-3 (LFA-3) (CEA/TRICOM). Two types of poxvirus vectors were developed: replication-competent recombinant vaccinia and replication-defective recombinant fowlpox. We have shown previously that a vaccine regimen composed of priming mice s.c. with recombinant vaccinia-CEA/TRICOM and boosting i.t. with recombinant fowlpox-CEA/TRICOM was superior to priming and boosting vaccinations using the conventional s.c. route in inducing T-cell responses specific for CEA. These studies also showed that CEA was needed to be present both in the vaccine and in the tumor for therapeutic effects.
To determine specific immune responses associated with vaccination-mediated tumor regression, CEA-transgenic mice bearing CEA(+) tumors were vaccinated with the CEA/TRICOM s.c./i.t. regimen, and T-cell immune responses were assessed.
In CEA(+) tumor-bearing mice vaccinated with the CEA/TRICOM s.c./i.t. regimen, T-cell responses could be detected not only to CEA encoded in vaccine vectors but also to other antigens expressed on the tumor itself: wild-type p53 and an endogenous retroviral epitope of gp70. Moreover, the magnitude of CD8(+) T-cell immune responses to gp70 was far greater than that induced to CEA or p53. Finally, the predominant T-cell population infiltrating the regressing CEA(+) tumor after therapy was specific for gp70.
These studies show that the breadth and magnitude of antitumor immune cascades to multiple antigens could be critical in the therapy of established tumors.
针对肿瘤相关抗原的癌症疫苗正在被研究用于肿瘤治疗。已经研究了多种策略，包括直接瘤内（i.t.）接种途径。对于表达癌胚抗原（CEA）作为模型肿瘤相关抗原的肿瘤，我们之前设计了痘病毒载体，其包含CEA以及三种T细胞共刺激分子B7-1、细胞间黏附分子-1（ICAM-1）和白细胞功能相关抗原-3（LFA-3）的转基因（CEA/TRICOM）。开发了两种痘病毒载体：具有复制能力的重组痘苗病毒和复制缺陷型重组禽痘病毒。我们之前已经表明，由用重组痘苗病毒-CEA/TRICOM皮下（s.c.）免疫小鼠并随后用重组禽痘病毒-CEA/TRICOM瘤内免疫增强组成的疫苗方案，在诱导针对CEA的特异性T细胞反应方面优于使用传统皮下途径进行免疫和免疫增强。这些研究还表明，为了产生治疗效果，疫苗和肿瘤中都需要存在CEA。
为了确定与疫苗接种介导的肿瘤消退相关的特异性免疫反应，用CEA/TRICOM皮下/瘤内方案对携带CEA(+)肿瘤的CEA转基因小鼠进行疫苗接种，并评估T细胞免疫反应。
在用CEA/TRICOM皮下/瘤内方案接种的CEA(+)荷瘤小鼠中，不仅可以检测到针对疫苗载体中编码的CEA的T细胞反应，还可以检测到针对肿瘤自身表达的其他抗原的反应：野生型p53和gp70的内源性逆转录病毒表位。此外，CD8(+) T细胞对gp70的免疫反应强度远大于对CEA或p53诱导的反应强度。最后，治疗后浸润消退的CEA(+)肿瘤的主要T细胞群体对gp70具有特异性。
这些研究表明，针对多种抗原的抗肿瘤免疫级联反应的广度和强度在已建立肿瘤的治疗中可能至关重要。
