Cork Cancer Research Centre, Mercy University Hospital and Leslie C Quick Jnr Laboratory, University College Cork, Cork, Ireland.
Cancer Gene Ther. 2010 Jul;17(7):501-11. doi: 10.1038/cgt.2010.8. Epub 2010 Feb 26.
Obstacles to effective immunotherapeutic anti-cancer approaches include poor immunogenicity of the tumour cells and the presence of tolerogenic mechanisms in the tumour microenvironment. We report an effective immune-based treatment of weakly immunogenic, growing solid tumours using a locally delivered immunogene therapy to promote development of immune effector responses in the tumour microenvironment and a systemic based T regulatory cell (Treg) inactivation strategy to potentiate these responses by elimination of tolerogenic or immune suppressor influences. As the JBS fibrosarcoma is weakly immunogenic and accumulates Treg in its microenvironment with progressive growth, we used this tumour model to test our combined immunotherapies. Plasmids encoding GM-CSF and B7-1 were electrically delivered into 100 mm(3) tumours; Treg inactivation was accomplished by systemic administration of anti-CD25 antibody (Ab). Using this approach, we found that complete elimination of tumours was achieved at a level of 60% by immunogene therapy, 25% for Treg inactivation and 90% for combined therapies. Moreover, we found that these responses were immune transferable, systemic, tumour specific and durable. Combined gene-based immune effector therapy and Treg inactivation represents an effective treatment for weakly antigenic solid growing tumours and that could be considered for clinical development.
有效免疫抗癌方法的障碍包括肿瘤细胞的免疫原性差和肿瘤微环境中存在耐受机制。我们报告了一种有效的免疫基于治疗弱免疫原性，生长的固体肿瘤使用局部递送免疫基因治疗以促进在肿瘤微环境中发展免疫效应反应和基于系统的 T 调节细胞（Treg）失活策略通过消除耐受或免疫抑制影响来增强这些反应。由于 JBS 纤维肉瘤是弱免疫原性的，并随着其微环境的逐渐生长而积累 Treg，因此我们使用这种肿瘤模型来测试我们的联合免疫疗法。编码 GM-CSF 和 B7-1 的质粒通过电传递到 100mm(3)肿瘤中；Treg 失活是通过全身给予抗 CD25 抗体（Ab）来实现的。使用这种方法，我们发现免疫基因治疗可使肿瘤完全消除率达到 60%，Treg 失活率为 25%，联合治疗率为 90%。此外，我们发现这些反应是可转移的、全身性的、肿瘤特异性的和持久的。基于基因的免疫效应因子联合治疗和 Treg 失活代表了一种治疗弱抗原性生长肿瘤的有效方法，可考虑用于临床开发。
