Department of Radiation Oncology, University of California at Davis, Sacramento, CA, USA.
J Immunotoxicol. 2012 Jul-Sep;9(3):248-58. doi: 10.3109/1547691X.2012.685527. Epub 2012 Jun 26.
Immunotherapy in the treatment of cancer is increasing, particularly with the recent FDA approval of sipuleucel-T and ipilimumab. The efficacy of anti-tumor immunotherapies has been modest compared to their theoretical and pre-clinical promise. This review evaluates the promise and pitfalls of immunotherapy and highlight some of the obstacles to improving anti-tumor immunotherapy: the need for technical refinement of therapies, the need for an increased understanding of how best to combine therapies with traditional cytotoxic therapies, the inability of patients to mount an effective immune response either due to disease burden or tumor induced immune suppression, the significant toxicities associated with many immunotherapies, and the lack of strongly immunogenic antigens required by many therapies. Further, antigen-non-specific immunotherapies, including cytokines such as interleukins and interferons, immuno-stimulatory agents such as CpG oligonucleotides, or BCG, antibodies targeted against receptors such as the agonistic CD40 or inhibitory CTLA-4 antibodies, and enzyme inhibitors such as those targeting cyclo-oxygenase or indolamine-2,3-dioxygenase are discussed. In addition, potential mechanisms of these therapies such as direct anti-tumor effects, reversal of immune suppression, activation of innate immunity, and antigen-non-specific T-cell activation are reviewed. We also appraise the potential of these antigen-non-specific therapies to overcome some of the previously described pitfalls of immunotherapy. Lastly, we discuss a recent series of studies from our laboratory demonstrating the importance of antigen-non-specific 'bystander activation' of memory T-lymphocytes by immunomodulatory therapies such as interleukin-2 and the antigen-non-specific anti-tumor effects of these cells.
免疫疗法在癌症治疗中的应用正在增加，特别是最近 FDA 批准了 sipuleucel-T 和 ipilimumab。与理论和临床前的预期相比，抗肿瘤免疫疗法的疗效并不显著。这篇综述评估了免疫疗法的前景和陷阱，并强调了改善抗肿瘤免疫疗法的一些障碍：需要对疗法进行技术改进，需要更好地了解如何将疗法与传统细胞毒性疗法相结合，由于疾病负担或肿瘤诱导的免疫抑制，患者无法产生有效的免疫反应，许多免疫疗法都存在显著的毒性，许多疗法缺乏所需的强免疫原性抗原。此外，还讨论了抗原非特异性免疫疗法，包括细胞因子（如白细胞介素和干扰素）、免疫刺激剂（如 CpG 寡核苷酸或卡介苗）、针对受体（如激动性 CD40 或抑制性 CTLA-4 抗体）的抗体，以及针对环氧化酶或吲哚胺-2,3-双加氧酶的酶抑制剂等。此外，还综述了这些疗法的潜在机制，如直接抗肿瘤作用、逆转免疫抑制、激活固有免疫和抗原非特异性 T 细胞激活。我们还评估了这些抗原非特异性疗法克服免疫疗法先前描述的一些陷阱的潜力。最后，我们讨论了我们实验室最近的一系列研究，这些研究表明免疫调节疗法（如白细胞介素-2）对记忆 T 淋巴细胞的抗原非特异性“旁观者激活”以及这些细胞的抗原非特异性抗肿瘤作用的重要性。
