Active specific immunotherapy of melanoma with allogeneic cell lysates. Rationale, results, and possible mechanisms of action.
Active specific immunotherapy of melanoma with allogeneic cell lysates. Rationale, results, and possible mechanisms of action.
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使用同种异体细胞裂解物对黑色素瘤进行主动特异性免疫治疗。
DOI：
10.1111/j.1749-6632.1993.tb44005.x
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发表时间：
1993
影响因子：
5.2
通讯作者：
Groshen,S
中科院分区：
文献类型：
--
作者：
Mitchell,MS;Harel,W;Kan-Mitchell,J;LeMay,LG;Goedegebuure,P;Huang,XQ;Hofman,F;Groshen,S
自1985年以来，我们进行了治疗性黑色素瘤疫苗（黑色素瘤治疗疫苗）的临床试验。选择具有互补特性的两种黑色素瘤细胞系的机械溶解物与辅助排毒相结合，并在第1、2、3、4和6周皮下注射一或两个疗程，然后在客观临床反应的患者中每月注射。106例患者中，20例临床肿块客观消退，5例完全缓解。中位反应持续时间为21个月。12例患者存活至少2年，中位生存期近3年。其中2例分别无病2年和6年。然而，并不一定要达到完全缓解才能增加生存率，大多数长期存活的患者有一个或多个（稳定的）残余结节。在这些个体中，疾病进程的速度明显减慢。血液中细胞毒性t淋巴细胞前体（pTC）水平的升高与临床反应相关。只有那些pTC升高的患者才有缓解。除了“经典的”CD8+ Tc， CD4+ Tc也从免疫患者的血液中克隆出来。两种类型的黑色素瘤特异性Tc都能杀死自体黑色素瘤，但不能匹配淋巴母细胞样细胞。同种异体黑色素瘤细胞系也被杀死，主要是HLA-A2/28和HLA-B12/44/45退行性限制。CD4+ Tc受HLA I类抗原的限制，可通过杀伤HLA ii类阴性黑色素瘤和抗I类抗体的阻断来判断。其他CD4+克隆均被抗hla I类或抗II类MHC单克隆抗体阻断，只有两个克隆仅被抗hla II类阻断。免疫史显示排斥反应的病变中有CD4+和CD8+ T细胞，但主要细胞是巨噬细胞，提示延迟型超敏反应可能是其机制。临床反应最常见于HLA-A2/28、-B12/44/45和c3患者，特别是当这些等位基因中有两个或两个以上存在时。这可能是由于(1)免疫黑色素瘤和患者黑色素瘤之间MHC抗原的相似性或(2)这些MHC分子在体内将黑色素瘤相关抗原呈递给Tc时的内在重要性。无论MHC表型如何，ifn - α 2b挽救了18例治疗失败的患者中的8例，可能是通过上调MHC和原位肿瘤上的肿瘤表位。
Since 1985, we have conducted clinical trials with a therapeutic melanoma vaccine (melanoma theraccine). Mechanical lysates of two melanoma cell lines chosen for their complementary characteristics were combined with the adjuvant DETOX and injected subcutaneously on weeks 1, 2, 3, 4, and 6 for one or two courses and then monthly in patients with objective clinical responses. Of 106 patients, 20 had objective clinical regression of tumor masses, 5 with complete responses. The median duration of response was 21 months. Twelve patients lived at least 2 years, with a median survival of nearly 3 years. Two of them are free of disease for> 2 and> 6 years, respectively. However, it was not necessary to achieve complete remissions to cause an increase in survival, and most of the long-surviving patients have one or more (stable) residual nodules. The pace of the disease process was clearly slowed in those individuals. A rise in the level of cytotoxic T-lymphocyte precursors in the blood (pTC) correlated with clinical response. Only those patients who had a rise in pTC had a remission. In addition to" classical" CD8+ Tc, CD4+ Tc were cloned from the blood of immunized patients. Melanoma-specific Tc of both types that killed autologous melanoma but not matched lymphoblastoid cells were detected. Allogeneic melanoma cell lines were also killed, with mainly HLA-A2/28 and HLA-B12/44/45 degenerate restriction. CD4+ Tc were restricted by HLA Class I antigens, as judged by their killing of HLA Class II-negative melanomas and blocking by anti-class I antibodies. Other CD4+ clones were blocked by both anti-HLA Class I or anti-Class II MHC monoclonal antibodies, and only two were blocked only by anti-HLA Class II. Immunohistory revealed CD4+ and CD8+ T cells in lesions under rejection, but the predominant cells were macrophages, suggesting delayed-type hypersensitivity as a possible mechanism. Clinical responses were found most often in patients with HLA-A2/28,-B12/44/45, and-C3, particularly when two or more of those alleles were present. This may have been due either to (1) similarity of MHC antigens between one of the immunizing melanomas and the patient's melanoma or (2) the intrinsic importance of these MHC molecules in presenting melanoma-associated antigens to Tc in vivo. IFN-alpha 2 b salvaged 8 of 18 patients who failed with the theraccine, regardless of MHC phenotype, perhaps through upregulation of MHC and tumor epitopes on the autochthonous tumor.