Lode H N, Xiang R, Duncan S R, Theofilopoulos A N, Gillies S D, Reisfeld R A
The Scripps Research Institute, Department of Immunology, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 1999 Jul 20;96(15):8591-6. doi: 10.1073/pnas.96.15.8591.
Induction, maintenance, and amplification of tumor-protective immunity after cytokine gene therapy is essential for the clinical success of immunotherapeutic approaches. We investigated whether this could be achieved by single-chain IL-12 (scIL-12) gene therapy followed by tumor-targeted IL-2 using a fusion protein containing a tumor-specific recombinant anti-ganglioside GD(2) antibody and IL-2 (ch14.18-IL-2) in a poorly immunogenic murine neuroblastoma model. Herein, we demonstrate the absence of liver and bone marrow metastases after a lethal challenge with NXS2 wild-type cells only in mice (five of six animals) vaccinated with scIL-12-producing NXS2 cells and given a booster injection of low-dose ch14.18-IL-2 fusion protein. This tumor-protective immunity was effective 3 months after initial vaccination, in contrast to control animals treated with a nonspecific fusion protein or an equivalent mixture of antibody and IL-2. Only vaccinated mice receiving the tumor-specific ch14.18-IL-2 fusion protein revealed a reactivation of CD8(+) T cells and subsequent MHC class I-restricted tumor target cell lysis in vitro. The sequential increase in the usage of TCR chains Vbeta11 and -13 in mouse CD8(+) T cells after vaccination and amplification with ch14.18-IL-2 suggests that the initial polyclonal CD8(+) T cell response is effectively boosted by targeted IL-2. In conclusion, we demonstrate that a successful boost of a partially protective memory T cell immune response that is induced by scIL-12 gene therapy could be generated by tumor-specific targeting of IL-2 with a ch14.18-IL-2 fusion protein. This approach could increase success rates of clinical cancer vaccine trials.
细胞因子基因治疗后诱导、维持和增强肿瘤保护性免疫对于免疫治疗方法的临床成功至关重要。我们在免疫原性较差的小鼠神经母细胞瘤模型中研究了是否可以通过单链IL-12（scIL-12）基因治疗，随后使用含有肿瘤特异性重组抗神经节苷脂GD(2)抗体和IL-2的融合蛋白（ch14.18-IL-2）进行肿瘤靶向IL-2治疗来实现这一目标。在此，我们证明，仅在接种产生scIL-12的NXS2细胞并给予低剂量ch14.18-IL-2融合蛋白加强注射的小鼠（六只动物中的五只）中，在用NXS2野生型细胞进行致死性攻击后未出现肝脏和骨髓转移。与用非特异性融合蛋白或抗体与IL-2的等效混合物治疗的对照动物相比，这种肿瘤保护性免疫在初次接种后3个月仍然有效。只有接受肿瘤特异性ch14.18-IL-2融合蛋白的接种小鼠在体外显示出CD8(+) T细胞的重新激活以及随后的MHC I类限制性肿瘤靶细胞裂解。接种疫苗并用ch14.18-IL-2扩增后，小鼠CD8(+) T细胞中TCR链Vbeta11和-13使用频率的依次增加表明，靶向IL-2有效地增强了初始多克隆CD8(+) T细胞反应。总之，我们证明，通过用ch14.18-IL-2融合蛋白对IL-2进行肿瘤特异性靶向，可以成功增强由scIL-12基因治疗诱导的部分保护性记忆T细胞免疫反应。这种方法可能会提高临床癌症疫苗试验的成功率。
