Whereas systemic IL12 is associated with potentially life-threatening toxicity, intratumoral delivery of IL12 through tavokinogene telseplasmid electroporation (tavo) is safe and can induce tumor regression at distant sites. The mechanism by which these responses are mediated is unknown but is presumed to result from a cellular immune response. In a phase II clinical trial of tavo (NCT01502293), samples from 29 patients with cutaneous melanoma with in-transit disease were assessed for immune responses induced with this treatment. Within the blood circulating immune cell population, we found that the frequencies of circulating PD-1+ CD4+ and CD8+ T cells declined with treatment. Circulating immune responses to gp100 were also detected following treatment as measured by IFNγ ELISpot. Patients with a greater antigen-specific circulating immune response also had higher numbers of CD8+ T cells within the tumor. Clinical response was also associated with increased intratumoral CD3+ T cells. Finally, intratumoral T-cell clonality and convergence were increased after treatment, indicating a focusing of the T-cell receptor repertoire. These results indicated that local treatment with tavo can induce a systemic T-cell response and recruit T cells to the tumor microenvironment.

中文翻译：

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晚期黑素瘤患者的瘤内质粒IL12电穿孔治疗可诱导全身性和瘤内T细胞反应。

全身性IL12与潜在的威胁生命的毒性相关，而通过tavokinogene端粒体电穿孔（tavo）在肿瘤内递送IL12是安全的，并且可以在远处诱发肿瘤消退。介导这些应答的机制尚不清楚，但推测是由细胞免疫应答引起的。在tavo的II期临床试验（NCT01502293）中，评估了来自29例运输途中皮肤黑素瘤患者的样本，以评估该疗法引起的免疫反应。在血液循环免疫细胞群中，我们发现循环PD-1 + CD4 +和CD8 + T细胞的频率随着治疗而下降。如IFNγELISpot所测量，在治疗后还检测到对gp100的循环免疫应答。具有更大的抗原特异性循环免疫应答的患者在肿瘤内也具有更高数量的CD8 + T细胞。临床反应还与肿瘤内CD3 + T细胞增加有关。最后，治疗后肿瘤内T细胞的克隆性和收敛性增加，表明T细胞受体库集中。这些结果表明，用tavo进行局部治疗可以诱导全身性T细胞应答，并将T细胞募集到肿瘤微环境中。