Gulley James L, Madan Ravi A, Pachynski Russell, Mulders Peter, Sheikh Nadeem A, Trager James, Drake Charles G
Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Washington University School of Medicine, St. Louis, MO, USA.
J Natl Cancer Inst. 2017 Apr 1;109(4). doi: 10.1093/jnci/djw261.
Immunotherapy is an important breakthrough in cancer. US Food and Drug Administration-approved immunotherapies for cancer treatment (including, but not limited to, sipuleucel-T, ipilimumab, nivolumab, pembrolizumab, and atezolizumab) substantially improve overall survival across multiple malignancies. One mechanism of action of these treatments is to induce an immune response against antigen-bearing tumor cells; the resultant cell death releases secondary (nontargeted) tumor antigens. Secondary antigens prime subsequent immune responses (antigen spread). Immunotherapy-induced antigen spread has been shown in clinical studies. For example, in metastatic castration-resistant prostate cancer patients, sipuleucel-T induced early immune responses to the immunizing antigen (PA2024) and/or the target antigen (prostatic acid phosphatase). Thereafter, most patients developed increased antibody responses to numerous secondary proteins, several of which are expressed in prostate cancer with functional relevance in cancer. The ipilimumab-induced antibody profile in melanoma patients shows that antigen spread also occurs with immune checkpoint blockade. In contrast to chemotherapy, immunotherapy often does not result in short-term changes in conventional disease progression end points (eg, progression-free survival, tumor size), which may be explained, in part, by the time taken for antigen spread to occur. Thus, immune-related response criteria need to be identified to better monitor the effectiveness of immunotherapy. As immunotherapy antitumor effects take time to evolve, immunotherapy in patients with less advanced cancer may have greater clinical benefit vs those with more advanced disease. This concept is supported by prostate cancer clinical studies with sipuleucel-T, PSA-TRICOM, and ipilimumab. We discuss antigen spread with cancer immunotherapy and its implications for clinical outcomes.
免疫疗法是癌症治疗领域的一项重要突破。美国食品药品监督管理局批准用于癌症治疗的免疫疗法（包括但不限于sipuleucel-T、伊匹单抗、纳武单抗、帕博利珠单抗和阿特珠单抗）显著提高了多种恶性肿瘤患者的总生存期。这些治疗方法的一种作用机制是诱导针对携带抗原的肿瘤细胞的免疫反应；由此产生的细胞死亡会释放次级（非靶向）肿瘤抗原。次级抗原引发后续的免疫反应（抗原扩散）。免疫疗法诱导的抗原扩散已在临床研究中得到证实。例如，在转移性去势抵抗性前列腺癌患者中，sipuleucel-T诱导了对免疫抗原（PA2024）和/或靶抗原（前列腺酸性磷酸酶）的早期免疫反应。此后，大多数患者对多种次级蛋白的抗体反应增强，其中几种在前列腺癌中表达且与癌症具有功能相关性。黑色素瘤患者中伊匹单抗诱导的抗体谱表明，免疫检查点阻断也会发生抗原扩散。与化疗不同，免疫疗法通常不会导致传统疾病进展终点（如无进展生存期、肿瘤大小）的短期变化，这可能部分是由于抗原扩散发生所需的时间。因此，需要确定免疫相关的反应标准，以更好地监测免疫疗法的有效性。由于免疫疗法的抗肿瘤作用需要时间来显现，对于癌症分期较低的患者，免疫疗法可能比癌症分期较高的患者具有更大的临床益处。前列腺癌使用sipuleucel-T、PSA-TRICOM和伊匹单抗的临床研究支持了这一概念。我们讨论了癌症免疫疗法中的抗原扩散及其对临床结果的影响。
