Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, Michigan.
Department of Medicine, University of Virginia Cancer Center, Charlottesville, Virginia.
Cancer Res Commun. 2024 Jul 1;4(7):1715-1725. doi: 10.1158/2767-9764.CRC-24-0112.
Sipuleucel-T is an autologous cellular immunotherapy that targets prostatic acid phosphatase (PAP) and is available for treatment of men with asymptomatic or minimally symptomatic metastatic castration-resistant prostate cancer (mCRPC). In this single-arm, two-cohort, multicenter clinical study, potential racial differences in immune responses to sipuleucel-T in men with mCRPC were explored. Patients' blood samples were obtained to assess serum cytokines, humoral responses, and cellular immunity markers before and after treatment. Baseline cumulative product parameters (total nucleated and CD54+ cell counts and CD54 upregulation) were evaluated. IgM titers against the immunogen PA2024, the target antigen PAP, prostate-specific membrane antigen (PSMA) and prostate-specific antigen (PSA) were quantified by ELISA. Cytotoxic T-lymphocyte activity was determined by ELISpots, and cytokine and chemokine concentrations were determined by Luminex.Twenty-nine African American (AA) men and 28 non-African American (non-AA) men with mCRPC received sipuleucel-T. Baseline total nucleated cell count, CD54+ cell count, CD54 expression, and cumulative product parameters were higher in non-AA men. Although PSA baseline levels were higher in AA men, there were no racial differences in IgM antibody and IFNγ ELISpots responses against PA2024, PAP, PSA, and PSMA before and after treatment. Expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells, and the levels of Th1 cytokine granulocyte-macrophage colony-stimulating factor and chemokines CCL4 and CCL5, were significantly higher in AA men before and/or after treatment. Despite no difference in the overall survival, PSA changes from baseline were significantly different between the two races. The data suggest that immune correlates in blood differ in AA and non-AA men with mCRPC pre- and post-sipuleucel-T.
Our novel findings of higher expression of co-stimulatory receptor ICOS on CD4+ and CD8+ T cells in African American patients with metastatic castrate-resistant prostate cancer (mCRPC) prior and post-sipuleucel-T suggest activation of CD4+ and CD8+ T cells. The data indicate that racial differences observed in these and other immune correlates before and after sipuleucel-T warrant additional investigation to further our understanding of the immune system in African American men and other men with mCRPC.
Sipuleucel-T 是一种针对前列腺酸性磷酸酶 (PAP) 的自体细胞免疫疗法，可用于治疗无症状或轻度症状转移性去势抵抗性前列腺癌 (mCRPC) 男性患者。在这项单臂、两队列、多中心临床研究中，探讨了 mCRPC 男性对 sipuleucel-T 的免疫反应中潜在的种族差异。在治疗前后，从患者的血液样本中获取血清细胞因子、体液反应和细胞免疫标志物，评估基线累积产物参数（总核细胞和 CD54+细胞计数和 CD54 上调）。通过 ELISA 定量测定针对免疫原 PA2024、靶抗原 PAP、前列腺特异性膜抗原 (PSMA) 和前列腺特异性抗原 (PSA) 的 IgM 滴度。通过 ELISpots 测定细胞毒性 T 淋巴细胞活性，并通过 Luminex 测定细胞因子和趋化因子浓度。29 名非裔美国 (AA) 男性和 28 名非非裔美国 (非-AA) 男性 mCRPC 患者接受了 sipuleucel-T 治疗。非 AA 男性的基线总核细胞计数、CD54+细胞计数、CD54 表达和累积产物参数较高。尽管 AA 男性的 PSA 基线水平较高，但在治疗前后，针对 PA2024、PAP、PSA 和 PSMA 的 IgM 抗体和 IFNγ ELISpots 反应无种族差异。在治疗前后，CD4+和 CD8+T 细胞上共刺激受体 ICOS 的表达以及 Th1 细胞因子粒细胞-巨噬细胞集落刺激因子和趋化因子 CCL4 和 CCL5 的水平在 AA 男性中均显著升高。尽管总体生存无差异，但 PSA 自基线的变化在两个种族之间存在显著差异。数据表明，在接受 sipuleucel-T 治疗前后，mCRPC 的 AA 和非 AA 男性的血液免疫相关性存在差异。
我们的新发现表明，接受 sipuleucel-T 治疗前后，转移性去势抵抗性前列腺癌 (mCRPC) 非裔美国患者 CD4+和 CD8+T 细胞上共刺激受体 ICOS 的高表达提示 CD4+和 CD8+T 细胞的激活。数据表明，在接受 sipuleucel-T 治疗前后，这些和其他免疫相关性的种族差异需要进一步研究，以进一步了解非裔美国男性和其他 mCRPC 男性的免疫系统。
