Novel Nanotechnologies and Molecular Imaging Approaches for Cancer Immunotherapy

大多数癌症 治疗需要连续给药以克服肿瘤的对数再生长。相比之下，通过肿瘤相关抗原（TAA）靶向癌症的T细胞可以扩增以获得初始临床效果，然后由于获得免疫记忆而在长时间间隔内自我维持和有效。在小鼠中的大量实验数据支持这些概念，并且有大量临床证据表明， 当针对TAA的T细胞介导的免疫被癌症疫苗、基于细胞的疗法或单克隆抗体激活时，癌症，特别是黑素瘤，经历持续缓解（1，4，5）。然而，这种应答的低频率和显示对免疫疗法的客观应答的肿瘤类型的有限谱令人失望。肿瘤通过阻断细胞死亡途径、通过抑制靶抗原的表达或通过产生免疫抑制微环境来进化抵抗免疫疗法的机制。最近的数据（6，7）表明，在一些患者中，这些耐药机制可以通过ACT与TCR基因治疗的联合来规避。这种新方法显著增加了表达有效抗肿瘤TCR的CTL的数量。我们和其他人假设这种方法将 显著提高ACT疗法对黑色素瘤患者和其他主要癌症的疗效。

Most cancer therapeutics require continuous dosing to overcome the logarithmic re-growth of tumors. In contrast, T cells targeted to cancer via tumor associated antigens (TAA), can expand for an initial clinical effect and, then to be self-sustained and effective over long intervals due to the acquisition of immunological memory. Ample experimental data in mice support these concepts and there is substantial clinical evidence that certain cancers, in particular melanoma, undergo sustained remissions when T cell mediated immunity against TAAs is activated by cancer vaccines, cell-based therapies or monoclonal antibodies (1,4,5). However, the low frequency of such responses and the limited spectrum of tumor types that show objective responses to immunotherapy have been disappointing. Tumors evolve mechanisms that resist immunotherapy by blocking cell death pathways, by suppressina the expression of target antigens or by generating immunosuppressive microenvironments. Recent data(6,7) suggest that, in some patients, these resistance mechanisms can be circumvented by combining ACT with TCR gene therapy. This novel approach dramatically increases the number of CTLs that express effective anti-tumor TCRs. We and others hypothesize that this approach will dramatically enhance the efficacy of the ACT therapy for melanoma patients, and for other major cancers.