Di Nicola Massimo, Carlo-Stella Carmelo, Mortarini Roberta, Baldassari Paola, Guidetti Anna, Gallino Gian Francesco, Del Vecchio Michele, Ravagnani Fernando, Magni Michele, Chaplin Paul, Cascinelli Natale, Parmiani Giorgio, Gianni Alessandro M, Anichini Andrea
Cristina Gandini Bone Marrow Transplantation Unit, Istituto Nazionale Tumori, Milan, Italy. dinicola@
Clin Cancer Res. 2004 Aug 15;10(16):5381-90. doi: 10.1158/1078-0432.CCR-04-0602.
Six American Joint Committee on Cancer stage IV melanoma patients were enrolled into a Phase I study of vaccination with autologous CD34(+)-derived dendritic cells transduced with a modified vaccinia Ankara virus encoding human tyrosinase gene (MVA-hTyr).
Patients received a first intravenous injection of 1 x 10(8) MVA-hTyr-transduced dendritic cells, followed by three s.c. injections at a 14-day interval.
Treatment was well tolerated, except for low-grade fever (three of six patients), mild erythema at injection site (five of six), and vitiligo (two of six). A partial response, involving shrinkage of an s.c. nodule, later surgically removed, was observed in 1 patient, who then remained disease-free (>850 days). By human lymphocyte antigen tetramer analysis, significant and often long-lasting increases in frequency of T cells directed to tyrosinase(368-376) but not to gp100(209-217) were documented in periphery of 4 of 5 HLA-A0201+ patients, a few days after vaccine administration. In addition, maturation phenotype of tyrosinase-specific T cell shifted toward the T effector memory/T terminally differentiate stages (CCR7(-)CD45RA(-/+)) in synchrony with the T-cell frequency peaks. By enzyme-linked immunospot in peripheral blood of five HLA-A0201+ patients, we found that the vaccine could induce interferon gamma-releasing effector cells directed to HLA-A0201/tyrosinase(368-376) and to vaccinia virus HLA-A0201/H3L(184-192) epitopes. Moreover, an interferon gamma response after vaccination was elicited even against the HLA-DRB1-1501/tyrosinase(386-406) epitope in one out of two HLA-A* DRB1-01501+ patients.
These results indicate that vaccination with MVA-hTyr-transduced dendritic cells is well tolerated, can possibly produce clinical responses, and activates tyrosinase- and vaccinia virus-specific T cells in vivo. These data suggest a broad utility of the MVA vector for targeting tumor-associated antigens to dendritic cells for tumor immunotherapy.
6例美国癌症联合委员会IV期黑色素瘤患者入组了一项I期研究，该研究采用编码人酪氨酸酶基因的改良安卡拉痘苗病毒（MVA-hTyr）转导的自体CD34(+)来源的树突状细胞进行疫苗接种。
患者首先静脉注射1×10(8)个经MVA-hTyr转导的树突状细胞，随后每隔14天进行3次皮下注射。
治疗耐受性良好，少数患者出现低热（6例中的3例）、注射部位轻度红斑（6例中的5例）和白癜风（6例中的2例）。1例患者出现部分缓解，表现为1个皮下结节缩小，随后手术切除，该患者随后无疾病进展（>850天）。通过人淋巴细胞抗原四聚体分析，在5例HLA-A0201+患者中的4例，疫苗接种后数天，外周血中针对酪氨酸酶(368 - 376)而非gp100(209 - 217)的T细胞频率显著且常呈持久增加。此外，酪氨酸酶特异性T细胞的成熟表型同步于T细胞频率峰值向T效应记忆/T终末分化阶段（CCR7(-)CD45RA(-/+))转变。通过对5例HLA-A0201+患者外周血进行酶联免疫斑点试验，我们发现该疫苗可诱导针对HLA-A0201/酪氨酸酶(368 - 376)和痘苗病毒HLA-A0201/H3L(184 - 192)表位的干扰素γ释放效应细胞。此外，在2例HLA-A* DRB1-01501+患者中的1例，接种疫苗后甚至引发了针对HLA-DRB1-1501/酪氨酸酶(386 - 406)表位的干扰素γ反应。
这些结果表明，用MVA-hTyr转导的树突状细胞进行疫苗接种耐受性良好，可能产生临床反应，并在体内激活酪氨酸酶和痘苗病毒特异性T细胞。这些数据表明MVA载体在将肿瘤相关抗原靶向树突状细胞用于肿瘤免疫治疗方面具有广泛用途。
