新辅助 PROSTVAC 治疗联合根治性前列腺切除术可增强前列腺癌患者肿瘤免疫微环境中的 T 细胞浸润。
Neoadjuvant PROSTVAC prior to radical prostatectomy enhances T-cell infiltration into the tumor immune microenvironment in men with prostate cancer.
机构信息
Genitourinary Malignancies Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
出版信息
J Immunother Cancer. 2020 Mar;8(1). doi: 10.1136/jitc-2020-000655.
BACKGROUND
Clinical trials have shown the ability of therapeutic vaccines to generate immune responses to tumor-associated antigens (TAAs). What is relatively less known is if this translates into immune-cell (IC) infiltration into the tumor microenvironment. This study examined whether neoadjuvant prostate-specific antigen (PSA)-targeted vaccination with PROSTVAC could induce T-cell immunity, particularly at the tumor site.
METHODS
An open-label, phase II study of neoadjuvant PROSTVAC vaccine enrolled 27 patients with localized prostate cancer awaiting radical prostatectomy (RP). We evaluated increases in CD4 and CD8 T-cell infiltrates (RP tissue vs baseline biopsies) using a six-color multiplex immunofluorescence Opal method. Antigen-specific responses were assessed by intracellular cytokine staining after in vitro stimulation of peripheral blood mononuclear cells with overlapping 15-mer peptide pools encoding the TAAs PSA, brachyury and MUC-1.
RESULTS
Of 27 vaccinated patients, 26 had matched prevaccination (biopsy) and postvaccination (RP) prostate samples available for non-compartmentalized analysis (NCA) and compartmentalized analysis (CA). Tumor CD4 T-cell infiltrates were significantly increased in postvaccination RP specimens compared with baseline biopsies by NCA (median 176/mm² vs 152/mm²; IQR 136-317/mm² vs 69-284/mm²; p=0.0249; median ratio 1.20; IQR 0.64-2.25). By CA, an increase in both CD4 T-cell infiltrates at the tumor infiltrative margin (median 198/mm² vs 151/mm²; IQR 123-500/mm² vs 85-256/mm²; p=0.042; median ratio 1.44; IQR 0.59-4.17) and in CD8 T-cell infiltrates at the tumor core (median 140/mm² vs 105/mm²; IQR 91-175/mm² vs 83-163/mm²; p=0.036; median ratio 1.25; IQR 0.88-2.09) were noted in postvaccination RP specimens compared with baseline biopsies. A total of 13/25 patients (52%) developed peripheral T-cell responses to any of the three tested TAAs (non-neoantigens); five of these had responses to more than one antigen of the three evaluated.
CONCLUSION
Neoadjuvant PROSTVAC can induce both tumor immune response and peripheral immune response.
TRIAL REGISTRATION NUMBER
NCT02153918.
背景
临床试验已经证明治疗性疫苗能够产生针对肿瘤相关抗原（TAA）的免疫反应。相对较少被人所知的是，这是否转化为免疫细胞（IC）浸润到肿瘤微环境中。本研究旨在检测新辅助前列腺特异性抗原（PSA）靶向疫苗 PROSTVAC 是否能够诱导 T 细胞免疫，特别是在肿瘤部位。
方法
一项新辅助 PROSTVAC 疫苗的开放性、二期研究纳入了 27 例等待根治性前列腺切除术（RP）的局限性前列腺癌患者。我们使用 Opal 六色多重免疫荧光法评估 CD4 和 CD8 T 细胞浸润（RP 组织与基线活检相比）的增加。通过体外用编码 TAA PSA、Brachyury 和 MUC-1 的重叠 15 -mer 肽池刺激外周血单核细胞，评估抗原特异性反应。
结果
在 27 例接受疫苗接种的患者中，26 例有匹配的疫苗接种前（活检）和接种后（RP）前列腺样本可供非分割分析（NCA）和分割分析（CA）。通过 NCA，与基线活检相比，接种后 RP 标本中的肿瘤 CD4 T 细胞浸润显著增加（中位数 176/mm² vs 152/mm²；IQR 136-317/mm² vs 69-284/mm²；p=0.0249；中位数比值 1.20；IQR 0.64-2.25）。通过 CA，在肿瘤浸润边缘处 CD4 T 细胞浸润的增加（中位数 198/mm² vs 151/mm²；IQR 123-500/mm² vs 85-256/mm²；p=0.042；中位数比值 1.44；IQR 0.59-4.17）和在肿瘤核心处 CD8 T 细胞浸润的增加（中位数 140/mm² vs 105/mm²；IQR 91-175/mm² vs 83-163/mm²；p=0.036；中位数比值 1.25；IQR 0.88-2.09）也在接种后 RP 标本中被观察到，与基线活检相比。25 例患者中有 13 例（52%）对三种测试的 TAA 中的任何一种（非新抗原）产生了外周 T 细胞反应；其中 5 例对三种评估抗原中的一种以上有反应。
结论
新辅助 PROSTVAC 可诱导肿瘤免疫反应和外周免疫反应。
试验注册号
NCT02153918。
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