Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer.
Neoadjuvant in situ vaccination with cowpea mosaic virus as a novel therapy against canine inflammatory mammary cancer.
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DOI：
10.1136/jitc-2021-004044
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发表时间：
2022-03
影响因子：
10.9
通讯作者：
Arias-Pulido H
中科院分区：
文献类型：
--
作者：
Alonso-Miguel D;Valdivia G;Guerrera D;Perez-Alenza MD;Pantelyushin S;Alonso-Diez A;Beiss V;Fiering S;Steinmetz NF;Suarez-Redondo M;Vom Berg J;Peña L;Arias-Pulido H
炎性乳腺癌（IMC）是人类炎性乳腺癌（IBC）的对应物，是犬乳腺肿瘤中最致命的形式。 IMC 患者缺乏特异性治疗且预后不佳。这项原理验证的临床前研究评估了新辅助瘤内（原位）空豇豆花叶病毒 (eCPMV) 免疫疗法对诊断为 IMC 的伴侣犬的有效性、安全性和对生存的影响。十只携带 IMC 的狗参加了这项研究。五只狗接受了药物治疗，五只狗每周接受新辅助原位 eCPMV 免疫治疗（每次注射 0.2-0.4mg），并在第二次 eCPMV 注射后接受药物治疗。通过减少肿瘤生长来评估疗效；血液和血浆的血液学和生物化学变化的安全性；和患者结果的生存分析。通过流式细胞术分析 eCPMV 诱导的血细胞免疫变化；通过CD3（T淋巴细胞）、CD20（B淋巴细胞）、FoxP3（Treg淋巴细胞）、髓过氧化物酶（MPO；中性粒细胞）、Ki-67（增殖指数，PI；肿瘤细胞增殖）和Cleaved Caspase-3（CC-3；凋亡）免疫组织化学评估肿瘤微环境的变化。两次新辅助原位 eCPMV 注射在第 14 天时使所有患者的肿瘤缩小，且没有出现全身不良事件。虽然 IMC 手术通常不是一种选择，但肿瘤大小的减小使得两名 IMC 患者可以接受手术。在外周血中，原位 eCPMV 免疫治疗与 Treg+/CD8+ 比率显着降低以及 CD8+ 颗粒酶 B+ T 细胞的变化相关，后者是一种滞后的预测生物标志物。在 TME 中，与治疗前的肿瘤样本相比，治疗后的肿瘤组织中观察到更高的中性粒细胞浸润和 MPO 表达、更低的肿瘤 Ki-67 PI、CD3+ 淋巴细胞增加、FoxP3+/CD3+ 比率降低（所有比较 p<0.04）以及 CC-3+ 免疫染色没有变化。与接受药物治疗的患者相比，接受 eCPMV 治疗的 IMC 患者的总体生存率具有统计学显着性 (p=0.033) 改善。新辅助原位 eCPMV 免疫疗法在 IMC 患者中显示出抗肿瘤功效并改善了生存率，且没有全身不良反应。 eCPMV 诱导的免疫细胞变化表明中性粒细胞是免疫反应的驱动因素。新辅助原位 eCPMV 免疫疗法可能是犬 IMC 的突破性免疫疗法，也是人类 IBC 患者未来潜在的免疫疗法。
Inflammatory mammary cancer (IMC), the counterpart of human inflammatory breast cancer (IBC), is the deadliest form of canine mammary tumors. IMC patients lack specific therapy and have poor outcomes. This proof-of-principle preclinical study evaluated the efficacy, safety, and effect on survival of neoadjuvant intratumoral (in situ) empty cowpea mosaic virus (eCPMV) immunotherapy in companion dogs diagnosed with IMC. Ten IMC-bearing dogs were enrolled in the study. Five dogs received medical therapy, and five received weekly neoadjuvant in situ eCPMV immunotherapy (0.2–0.4 mg per injection) and medical therapy after the second eCPMV injection. Efficacy was evaluated by reduction of tumor growth; safety by hematological and biochemistry changes in blood and plasma; and patient outcome by survival analysis. eCPMV-induced immune changes in blood cells were analyzed by flow cytometry; changes in the tumor microenvironment were evaluated by CD3 (T lymphocytes), CD20 (B lymphocytes), FoxP3 (Treg lymphocytes), myeloperoxidase (MPO; neutrophils), Ki-67 (proliferation index, PI; tumor cell proliferation), and Cleaved Caspase-3 (CC-3; apoptosis) immunohistochemistry. Two neoadjuvant in situ eCPMV injections resulted in tumor shrinkage in all patients by day 14 without systemic adverse events. Although surgery for IMC is generally not an option, reduction in tumor size allowed surgery in two IMC patients. In peripheral blood, in situ eCPMV immunotherapy was associated with a significant decrease of Treg+/CD8+ ratio and changes in CD8+Granzyme B+ T cells, which behave as a lagging predictive biomarker. In the TME, higher neutrophilic infiltration and MPO expression, lower tumor Ki-67 PI, increase in CD3+ lymphocytes, decrease in FoxP3+/CD3+ ratio (p<0.04 for all comparisons), and no changes in CC-3+ immunostainings were observed in post-treatment tumor tissues when compared with pretreatment tumor samples. eCPMV-treated IMC patients had a statistically significant (p=0.033) improved overall survival than patients treated with medical therapy. Neoadjuvant in situ eCPMV immunotherapy demonstrated anti-tumor efficacy and improved survival in IMC patients without systemic adverse effects. eCPMV-induced changes in immune cells point to neutrophils as a driver of immune response. Neoadjuvant in situ eCPMV immunotherapy could be a groundbreaking immunotherapy for canine IMC and a potential future immunotherapy for human IBC patients.
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DOI：
10.2460/javma.235.8.967
发表时间：
2009-10-15
影响因子：
1.9
作者：
Marconato, Laura;Romanelli, Giorgio;Zini, Eric
通讯作者：
Zini, Eric
影响因子：
2.2
作者：
Clemente, M.;De Andres, P. J.;Perez-Alenza, M. D.
通讯作者：
Perez-Alenza, M. D.
DOI：
10.2460/javma.2001.219.1110
发表时间：
2001-10-15
期刊：
JOURNAL OF THE AMERICAN VETERINARY MEDICAL ASSOCIATION
影响因子：
--
作者：
Alenza, MDP;Tabanera, E;Peña, L
通讯作者：
Peña, L
影响因子：
2.1
作者：
Alonso-Miguel, Daniel;Valdivia, Guillermo;Perez-Alenza, Maria Dolores
通讯作者：
Perez-Alenza, Maria Dolores
影响因子：
10.3
作者：
Hance, KW;Anderson, WF;Levine, PH
通讯作者：
Levine, PH