Division of Oncology, Department of Medicine, University of Washington, 825 Eastlake Ave E, G4830, Seattle, WA, 98109-1023, USA.
Clinical Research Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Ave N, D5-100, Seattle, WA, 98109-1024, USA.
Curr Treat Options Oncol. 2021 Jan 12;22(2):13. doi: 10.1007/s11864-020-00808-x.
Due to its immunosuppressive tumor microenvironment, prostate cancer has historically been difficult to treat with immuno-oncology approaches. Other than pembrolizumab, which is now regulatory-approved for all microsatellite instability (MSI)-high and tumor mutational burden (TMB)-high advanced solid tumors, sipuleucel-T is the only immunotherapeutic agent approved by the US Food and Drug Administration (FDA) for prostate cancer. However, sipuleucel-T efficacy is optimal for select patients with indolent metastatic castration-resistant prostate cancer. Although manipulation of immune regulation by blocking immune checkpoints has led to substantial benefit in many cancers, experience with single-agent CTLA-4 and PD-1 or PD-L1 antibodies has shown limited effect for the majority of patients with prostate cancer, especially when administered as monotherapy. Combination therapies are now being attempted, in addition to enrichment strategies employing patient clinicopathologic and biologic characteristics that may heighten responses to immuno-oncology treatment, such as PD-L1 expression, TMB, MSI status, and alterations in CDK12. More work is needed to overcome the immune-exclusive barriers in prostate cancer, such as relatively low TMB, increased activity of myeloid-derived suppressor cells (MDSCs) and regulatory T cells, and defects in major histocompatibility complex (MHC) class I expression and interferon (IFN)-1 signaling. A promising approach and the likely next step in immuno-oncology for prostate cancer involves forced direction to markers expressed by prostate cancer tumor cells, such as prostate-specific membrane antigen (PSMA), that bypass the typical requirements for MHC class I interaction. The future will incorporate bispecific antibodies and chimeric antigen receptor (CAR)-T cells, potentially targeted towards phenotypic markers identified by next-generation PET imaging as part of the next wave of "precision medicine" in prostate cancer. Ultimately, we believe that the immune-exclusive prostate cancer tumor microenvironment can be overcome, and that patient outcomes can be enhanced through these more refined immuno-oncology approaches.
由于前列腺癌的免疫抑制肿瘤微环境，其一直难以通过免疫肿瘤学方法进行治疗。除了现已被监管机构批准用于所有微卫星不稳定（MSI）高和肿瘤突变负担（TMB）高的晚期实体瘤的 pembrolizumab 外，sipuleucel-T 是唯一被美国食品和药物管理局（FDA）批准用于前列腺癌的免疫治疗药物。然而，sipuleucel-T 的疗效对于选择的惰性转移性去势抵抗性前列腺癌患者最佳。尽管通过阻断免疫检查点来操纵免疫调节在许多癌症中带来了实质性的益处，但单药 CTLA-4 和 PD-1 或 PD-L1 抗体的经验表明，对于大多数前列腺癌患者，特别是当作为单药治疗时，效果有限。除了采用可能增强对免疫肿瘤治疗反应的患者临床病理和生物学特征的富集策略外，目前正在尝试联合治疗，例如 PD-L1 表达、TMB、MSI 状态和 CDK12 改变。需要做更多的工作来克服前列腺癌中的免疫排他性障碍，例如相对较低的 TMB、髓源性抑制细胞（MDSC）和调节性 T 细胞活性增加，以及主要组织相容性复合体（MHC）I 类表达和干扰素（IFN）-1 信号的缺陷。一种有前途的方法，也是前列腺癌免疫肿瘤学的下一步，涉及到迫使针对前列腺癌细胞表达的标志物，如前列腺特异性膜抗原（PSMA），从而绕过 MHC I 类相互作用的典型要求。未来将包括双特异性抗体和嵌合抗原受体（CAR）-T 细胞，可能针对下一代 PET 成像识别的表型标志物作为前列腺癌“精准医学”的下一波的一部分。最终，我们相信可以克服免疫排他性前列腺癌肿瘤微环境，并且可以通过这些更精细的免疫肿瘤学方法来增强患者的治疗效果。
