Medicine, University of California San Francisco, San Francisco, California, USA.
San Francisco State University, San Francisco, California, USA.
J Immunother Cancer. 2020 May;8(1). doi: 10.1136/jitc-2019-000368.
CTLA-4 blockade with ipilimumab is Food and Drug Administration-approved for melanoma as a monotherapy and has been shown to modulate the circulating T-cell repertoire. We have previously reported clinical trials combining CTLA-4 blockade with granulocyte-macrophage colony-stimulating factor (GM-CSF) in metastatic melanoma patients and in metastatic castration resistant prostate cancer (mCRPC) patients. Here, we investigate the effect that cancer type has on circulating T cells in metastatic melanoma and mCRPC patients, treated with ipilimumab and GM-CSF.
We used next-generation sequencing of T-cell receptors (TCR) to compare the circulating T cells of melanoma and mCRPC patients receiving the same treatment with ipilimumab and GM-CSF by Wilcoxon rank sum test. Flow cytometry was utilized to investigate specific T-cell populations. TCR sequencing results were correlated with each T-cell subpopulation by Spearman's rank correlation coefficient. Of note, 14 metastatic melanoma patients had samples available for TCR sequencing and 21 had samples available for flow cytometry analysis; 37 mCRPC patients had samples available for sequencing of whom 22 have TCR data available at both timepoints; 20 of these patients had samples available for flow cytometry analysis and 16 had data available at both timepoints.
While melanoma and mCRPC patients had similar pretreatment circulating T-cell counts, treatment induces greater expansion of circulating T cells in melanoma patients. Metastatic melanoma patients have a higher proportion of clones that increased more than fourfold after the treatment compared with mCRPC patients (18.9% vs 11.0%, p=0.017). Additionally, melanoma patients compared with mCRPC patients had a higher ratio of convergent frequency (1.22 vs 0.60, p=0.012). Decreases in clonality induced by treatment are associated with baseline CD8+ T-cell counts in both patient groups, but are more pronounced in the melanoma patients (r=-0.81, p<0.001 vs r=-0.59, p=0.02).
NCT00064129; NCT01363206.
CTLA-4 阻断剂伊匹单抗已获美国食品和药物管理局批准，可作为单一疗法用于治疗黑色素瘤，其作用机制为调节循环 T 细胞库。我们先前报道过 CTLA-4 阻断剂联合粒细胞巨噬细胞集落刺激因子（GM-CSF）治疗转移性黑色素瘤和转移性去势抵抗性前列腺癌（mCRPC）患者的临床试验。在此，我们研究了癌症类型对接受伊匹单抗和 GM-CSF 治疗的转移性黑色素瘤和 mCRPC 患者循环 T 细胞的影响。
我们使用 T 细胞受体（TCR）的下一代测序技术，通过 Wilcoxon 秩和检验比较了接受相同伊匹单抗和 GM-CSF 治疗的黑色素瘤和 mCRPC 患者的循环 T 细胞。我们使用流式细胞术研究了特定的 T 细胞群。通过 Spearman 秩相关系数将 TCR 测序结果与每个 T 细胞亚群相关联。值得注意的是，14 名转移性黑色素瘤患者的样本可用于 TCR 测序，21 名患者的样本可用于流式细胞术分析；37 名 mCRPC 患者的样本可用于测序，其中 22 名患者在两个时间点均有 TCR 数据可用；20 名患者的样本可用于流式细胞术分析，其中 16 名患者在两个时间点均有数据可用。
尽管黑色素瘤和 mCRPC 患者的预处理循环 T 细胞计数相似，但治疗可使黑色素瘤患者的循环 T 细胞有更大程度的扩增。与 mCRPC 患者相比，转移性黑色素瘤患者中有更多的克隆在治疗后增加了四倍以上（18.9%比 11.0%，p=0.017）。此外，与 mCRPC 患者相比，黑色素瘤患者的趋同频率更高（1.22 比 0.60，p=0.012）。在两个患者组中，治疗诱导的克隆性降低与基线 CD8+T 细胞计数相关，但在黑色素瘤患者中更为显著（r=-0.81，p<0.001 比 r=-0.59，p=0.02）。
NCT00064129；NCT01363206。
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