Sipuleucel-T is an autologous cellular immunotherapy that induces an immune response targeted against prostatic acid phosphatase (PAP) to treat asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer. In the phase III IMPACT study, sipuleucel-T was associated with a statistically significantly increased overall survival (OS) (median = 4.1 months) vs placebo. Patients with baseline prostate-specific antigen levels in the lowest quartile (≤22.1 ng/mL) exhibited a 13-month improvement in OS with sipuleucel-T. Together, this led sipuleucel-T to be approved and recommended as first-line therapy in various guidelines for treatment of metastatic castration-resistant prostate cancer. This review discusses the varied findings about the mechanisms of action of sipuleucel-T, bringing them together to form a more coherent picture. These pieces include inducing a statistically significant increase in antigen-presenting cell activation; inducing a peripheral immune response specific to the target (PAP) and/or immunizing (PA2024) antigens; stimulating systemic cytotoxic T-lymphocyte activity; and mediating antigen spread (ie, increased antibody responses to secondary proteins in addition to PAP and PA2024). Each of these pieces individually correlates with OS. Sipuleucel-T also traffics T cells to the prostate and is associated with long-term immune memory such that a second course of treatment induces an anamnestic immune response. Prostate cancer does not have a strongly inflamed microenvironment, thus its response to immune checkpoint inhibitors is limited. Because sipuleucel-T is able to traffic T cells to the tumor, it may be an ideal combination partner with immunotherapies including immune checkpoint inhibitors or with radiation therapy.

中文翻译：

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将各个部分组合在一起：完成 Sipuleucel-T 的作用拼图机制。

Sipuleucel-T 是一种自体细胞免疫疗法，可诱导针对前列腺酸性磷酸酶 (PAP) 的免疫反应，以治疗无症状或症状轻微的转移性去势抵抗性前列腺癌。在 III 期 IMPACT 研究中，与安慰剂相比，sipuleucel-T 与总体生存期 (OS) 显着增加（中位值 = 4.1 个月）相关，具有统计学意义。基线前列腺特异性抗原水平处于最低四分位 (≤22.1 ng/mL) 的患者在使用 sipuleucel-T 后表现出 13 个月的 OS 改善。总之，这使得 sipuleucel-T 在各种转移性去势抵抗性前列腺癌治疗指南中获得批准并推荐为一线疗法。这篇综述讨论了有关 sipuleucel-T 作用机制的各种发现，并将它们汇总在一起形成一个更加连贯的图景。这些部分包括诱导抗原呈递细胞活化的统计显着增加；诱导针对靶标（PAP）和/或免疫（PA2024）抗原的外周免疫应答；刺激全身细胞毒性 T 淋巴细胞活性；介导抗原扩散（即，除了 PAP 和 PA2024 之外，还增加对次级蛋白的抗体反应）。这些部分中的每一个都与操作系统单独相关。Sipuleucel-T 还将 T 细胞运输到前列腺，并与长期免疫记忆相关，因此第二个疗程会诱导记忆性免疫反应。前列腺癌没有强烈炎症的微环境，因此其对免疫检查点抑制剂的反应有限。由于 sipuleucel-T 能够将 T 细胞运输至肿瘤，因此它可能是免疫疗法（包括免疫检查点抑制剂）或放射疗法的理想组合伙伴。