冷冻消融 Cryoablation
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• Preserves intracellular contents via cell death by necrosis （冷冻）通过使细胞因坏死/死亡来保存细胞内内容物
• Intracellular contents (Damage Associated Molecular Patterns DAMPs) will be fagocytized by antigen presenting cells (APC) and presenteted to T cells to elicit a tumor specific immune reaction 细胞内内容物(损伤相关的分子模式，DAMPs)将被抗原提呈细胞(APC)吞噬，并到街道T细胞以引起肿瘤特异性免疫反应
• Abscopal effect of cryoablation occurs infrequent 冷冻的远位（伴随）效果并不常见
• May be enhanced with immunostiumulants 通过免疫刺激可以增强
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1. Sabel MS. Cryo-immunology: a review of the literature and proposed mechanisms for stimulatory versus suppressive immune responses. Cryobiology. 2009 Feb;58(1):1–11.
2. Chu KF, Dupuy DE. Thermal ablation of tumours: biological mechanisms and advances in therapy. Nat Rev Cancer. 2014 Mar;14(3):199–208.
3. Joosten JJ, et al. In vivo destruction of tumor tissue by cryoablation can induce inhibition of secondary tumor growth: an experimental study. Cryobiology. 2001 Feb;42(1):49–58.
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MEDLINE 检索
• 时间 2001-2017
• 资料收集主要目标 Data collection:
• 免疫系统与冷冻消融之间的协调作用 Synergy between cryoablation and the immune system
• 冷冻消融和免疫治疗（冷冻治疗+免疫治疗） Cryoablation and immunotherapy
• 肿瘤组织的冷冻效果 Effect of cryoablation on tumor tissue
• 促进（刺激）免疫反应的最佳冷冻消融技术 Best cryoablation technique to create immune response
• 检索词 Keywords:
• Cryoablation（冷冻消融）, immune system（免疫系统）, immunotherapy（免疫治疗）, melanoma（黑色素瘤）, glioma（神经胶质瘤） 和 cancer（癌症）*
排除标准 EXCLUSION
• 冷冻治疗联合其它治疗 Combination of cryoablation with other interventional modalities
• 主要终点不符合资料收集标准目标 Primary endpoint doesn’t match the data collection criteria
• 非全文的文章 No full text article available
结果：
44篇文章 TOTAL OF 44 ARTICLES INCLUDED
• 26篇 临床前试验 26 preclinical articles
• 18篇临床文章 18 clinical articles
乳腺癌 BREAST CANCER
临床前研究 PRECLINICAL
• After cryoablation, re-challenge of the mice with the primary tumorcells results in 70% less tumor development compared to surgerical treated mice
冷冻消融后，与手术治疗的小鼠相比，再次刺激原发肿瘤细胞的小鼠导致肿瘤发展减少70%
• 100% freeze cycle improves overall survival and reduces pulmonary metastasis compared to surgery or 20% freeze cycle in mice
小鼠比较20%的冷冻周期或外科手术，100%的冷冻周期改善整体生存率和减少肺转移
• Combination of cryoablation with CpG nucleotide (bacteria) reduces secondary tumor growth and tumor recurrence
冻消融联合CpG核苷酸（细菌）可减少继发性肿瘤生长和肿瘤复发
临床研究 CLINICAL
• Cryoablation + Ipililumab (CTLA4-i) is safe before mastectomy (early stage BC)
冷冻切除术+伊利单抗(CTLA4-i)在乳房切除术前是安全的(乳腺癌早期)
• T cell sequencing shows decrease in T cells with more diversity
T细胞测序显示T细胞减少但更多样化
• Natural killer (NK) cell therapy + cryoablation is safe and significantly improves overall survival (stage III/IV recurrent BC)
自然杀伤细胞（NK细胞）+ 冷冻消融显著改善整体生存率（III/IV期乳腺癌）
• Cryoablation of metastase + Dendritic cells (DC) improves overal survival compared to cryo + chemo or cryo alone (mBC)
比较冷冻+化疗或单独冷冻消融治疗， 乳腺癌转移性病变的冷冻消融+突触细胞改善整体生存率
• Cryoablation did not elict any immune response on cytokine level (mBC)
冷冻并不能在细胞水平提升任何免疫反应
前列腺癌 PROSTATE CANCER
临床前研究 PRECLINICAL
• Cryoablation + CTLA -4 antibodies: 冷冻治疗+CTLA-4 抗体
• Increases survival with a reduction of distant metastasis 减少远处转移而增加生存率
• Tumor tissue shows an increased infiltration of CD 4 + and CD 8+ with a reduction of Tregs 肿瘤组织显示伴随淋巴调节细胞减少，CD4+和CD8+的浸润增加
• Trimodal therapy of cryoablation + androgen deprivation therapy + PD-1 blockade delayed tumor growth and increased survival benefit compared to therapies alone
比较单独冷冻治疗，冷冻消融三联治疗+雄激素去势治疗+PD1阻断，延迟肿瘤生长和增加生存
临床研究 CLINICAL
• Post cryoablation tissue showed declined Treg levels compared to healthy volunteers (T1 Pca) and higher levels of TNF-α and IFN-γ in high risk prostate patients
与健康志愿者相比，前列腺癌（T）冷冻消融后组织显示调节淋巴细胞（Treg）水平下降，高危前列腺患者的TNF-α和IFN-γ水平升高
• Cryoablation plus GM-CSF increased IFN-γ secreting T cells and median time to disease progression of 18 months in 12 metastatic hormone refractory prostate patients
在12例转移性激素难治性前列腺患者中，冷冻消融术加集落细胞刺激因子（GM-CSF）增加了IFN-γ分泌T细胞和疾病进展的中位时间为18个月
• Addition of cryoablation to androgen deprivation significantly improved survival (mPCa)
冷冻消融治疗和雄激素去势治疗显著改善转移性前列腺癌的生存期
肺癌 LUNG CANCER
临床前研究 PRECLINICAL
• Cryoablation + DC cells significantly prolonged survival with protection to secondary tumors and higher levels of effector memorary T cells
冷冻消融术+DC细胞显著延长了生存期，可保护继发性肿瘤和更高水平的效应记忆T细胞
• Cryoablation + CpG-ODN + DC cells elevated CD4+, CD8+ cells and cytokines IL-12 IFN-γ TNF-α
冷冻消融术+CpG-ODN（CpG寡脱氧核苷酸）+DC细胞提高了CD4+、CD8+细胞和细胞因子IL-12IFN-γTNF-α
• Best immune response was achieved after 2 cycles of cryoablation compared to 1 and 3 cycles of cryoablation
与1个和3个周期的冷冻消融相比，2个周期的冷冻消融后获得了最佳的免疫反应
临床研究 CLINICAL
• Cryoablation + NK cell therapy improved response rate compared to cryoablation alone (adv NSLC)
与单独冷冻消融(advNSLC)相比，冷冻消融+NK细胞治疗提高了反应率
• Cryoablation + Gefitinib improved 1 year survival rate compared to gefitinib alone (adv NSLC)
与单独使用吉非替尼(advNSLC)相比，冷冻消融术+吉非替尼提高了1年生存率
• Cryoablation before DC-CIK therapy and chemothearpy improved overal survival compared to chemotherapy alone (metastatic NSLC)31
与单独化疗(转移性非小细胞肺癌NSLC) 相比，DC-CIK治疗前的冷冻消融术和化疗能力改善了总体生存率
黑色素瘤 MELANOMA
临床前研究 PRECLINICAL
• Cryoablation creates a tumor specific immune response, via DC maturation, for partial protecting against re-challenge of the primary tumor
冷冻消融术通过DC成熟产生肿瘤特异性免疫反应，以部分保护原发肿瘤的再刺激
• The synergy between cryoablation + CpG oligodeoxynucleotide increases local and systemic effect for protection against primairy tumor and micrometastases outgrow
冷冻消融+CpG寡脱氧核苷酸（免疫辅助制剂）之间的协同作用增加了局部和全身保护原发肿瘤和微转移的作用
• Timing of CpG was important for cross representation of the DC to determine anti tumor immunity
CpG的时间对于DC的跨过呈递对确定抗肿瘤免疫非常重要
• The combination of anti ALCAM+ cells + cryoablation + anti CTLA 4 antibodies decreased tumor growth and metastatic load and survival over monotherapy
与单药治疗相比，抗ALCAM+细胞+冷冻消融+抗CTLA4抗体联合降低肿瘤生长和转移负荷和生存
临床研究 CLINICAL
• In patients with unresectable metastatic melanoma cryoablation + GM-CSF was safe and well torelated
其它肿瘤 OTHER
临床前研究 PRECLINICAL
• 7 preclinical studies used subcutaneously injected C6 Glioma cells in mice and rats reporting an enhancement of the immune system after cryoablation
7项临床前研究使用小鼠和大鼠皮下注射C6胶质瘤细胞，显示冷冻消融后免疫系统增强
• When cryoablation was combined with immunostimulants an improvement in survival was seen compared to cryoablation alone
当冷冻消融术与免疫刺激剂联合使用时，与单独使用冷冻消融术相比，生存率有所改善
• Cryoablation + Krestin (polysaccharide) of metastatic liver cancer reduced levels of IL-4 and IL10
转移性肝癌的冷冻消融术+Krestin（多糖）降低了IL-4和IL10的水平
临床研究 CLINICAL
• Cryoablation + NK cell therapy or DC-CIK cell therapy was safe and enhanced the immune system and increased survival (mHCC)
冷冻消融术+NK细胞治疗或DC-CIK细胞治疗是安全的，可增强免疫系统，提高生存率(mHCC)
结论
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• 30/44 articles combined immunostimulants with cryoablation.
30/44篇文章联合使用了免疫刺激剂和冷冻消融术。
• 5 articles used 2 immunostimulants.
5篇文章使用了2种免疫刺激剂。
• CpG ODN mostly used as immunostimulant.
CpGODN多作为免疫刺激剂使用。
• Microbacterial DNA.
微生物DNA
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