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。相反，通过肿瘤相关抗原(TAA)靶向肿瘤的T细胞可以在最初的临床效果下扩增，然后由于获得免疫记忆而在很长一段时间内自我维持和有效。在小鼠身上的大量实验数据支持这些概念，并且有大量的临床证据表明 癌症，特别是黑色素瘤，当T细胞介导的针对TAA的免疫被癌症疫苗、基于细胞的治疗或单抗激活时，持续缓解(1，4，5)。然而，这种反应的低频率和对免疫治疗表现出客观反应的肿瘤类型的有限光谱一直令人失望。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治疗的机制。最近的数据(6，7)表明，在一些患者中，通过联合ACT和TCR基因治疗可以绕过这些耐药机制。这一新方法极大地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 极大地提高了ACT治疗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.