Limited antitumor T cell response in melanoma patients vaccinated with interleukin-2 gene-transduced allogeneic melanoma cells
Limited antitumor T cell response in melanoma patients vaccinated with interleukin-2 gene-transduced allogeneic melanoma cells
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DOI：
10.1089/hum.1996.7.16-1955
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发表时间：
1996-10-20
影响因子：
4.2
通讯作者：
Parmiani, G
中科院分区：
文献类型：
--
作者：
Arienti, F;SuleSuso, J;Parmiani, G
我们已经用HLA-A2相容的人黑色素瘤细胞系免疫晚期黑色素瘤患者，该细胞系经遗传修饰以释放白细胞介素-2（IL-2），以引发或增加T细胞介导的抗黑色素瘤反应，该反应可能影响远处病变。12名IV期患者在第1、13、26和55天皮下注射IL-2基因转导和辐照的黑色素瘤细胞，剂量为5或15 × 107个细胞。局部和全身毒性均为轻度，包括接种部位的一过性红斑;少数患者出现发热。记录了三种混合反应。7例患者可进行免疫学研究评价。与不同的同种异体HLA-A2匹配的黑色素瘤细胞系作为刺激物和靶进行的混合肿瘤淋巴细胞培养显示，与接种前相比，接种后获得的外周血淋巴细胞（PBL）中的MHC限制性细胞毒性增加，但MHC限制性细胞毒性无变化。酪氨酸酶368-376肽的识别增加发生在1例患者的接种后PBL中，而gp 100 280-288肽的识别微弱增加在另1例患者中可检测到;这2例患者还识别了gp 100 457-466肽。在体外，用唯一可用的自体黑色素瘤细胞系刺激后，在接种后但未在接种前PBL中发现具有自体肿瘤特异性细胞毒性和释放干扰素-γ（IFN-γ）能力的CD 4（+）细胞。在同一患者以及另一名患者中，有限稀释分析显示，疫苗接种导致黑色素瘤特异性细胞毒性T淋巴细胞（CTE）前体的频率增加。这些结果表明，用局部释放IL-2的细胞接种可以扩大针对自体未转导肿瘤抗原的T细胞应答，尽管这种应答发生在所研究的少数黑素瘤患者中。
We have immunized advanced melanoma patients with a HLA-A2-compatible human melanoma line genetically modified to release interleukin-2 (IL-2), to elicit or increase a T cell-mediated anti-melanoma response that may affect distant lesions. Twelve stage-IV patients were injected subcutaneously at days 1, 13, 26, and 55 with IL-2 gene-transduced and irradiated melanoma cells at doses of 5 or 15 x 10(7) cells. Both local and systemic toxicities were mild, consisting of transient erythema at the vaccination site; fever occurred in a minority of patients. Three mixed responses were recorded. Seven patients were evaluable for immunological studies. Mixed tumor-lymphocyte cultures carried out with different allogeneic HLA-A2-matched melanoma lines as stimulators and targets revealed an increase in the MHC-unrestricted, but no changes in the MHC-restricted, cytotoxicity in peripheral blood lymphocytes (PBL) obtained after vaccination as compared with those obtained before vaccination. Increased recognition of the tyrosinase 368-376 peptide occurred in postvaccination PBL of one patient, whereas a weak increase in recognition of the gp100 280-288 peptide was detectable in another patient; these 2 patients also recognized the gp100 457-466 peptide. After in vitro, stimulation with the only available autologous melanoma line, CD4(+) cells with autologous tumor-specific cytotoxicity and ability to release interferon-gamma (IFN-gamma) were found in post- but not in pre-vaccination PBL. In the same patient, as well as in another patient, limiting dilution analysis showed that vaccination resulted in an increased frequency of melanoma-specific cytotoxic T lymphocyte (CTE) precursors. These results indicate that vaccination with cells releasing IL-2 locally can expand a T cell response against antigen(s) of autologous, untransduced tumor, although this response occurred in a minority of the melanoma patients studied.