冷冻+免疫治疗在很多肿瘤中使患者受益Lessons learned from « a pilot study of preoperative single dose ipilimumab and /or cryoablation in women with early stage breast cancer with
comprehensive immune profiling » Mc Arthur HL et al Clin cancer Research 22 (23): 5729-5737 2016
• Tested in a pilot study in melanoma – 16 pats 75% DCR and PFS was 57% at 6 months
黑色素瘤初步研究证实-6个月时，16个患者DCR75%, PFS57% • Tested in a retrospective trial in pancreatic adenocarcinoma 胰腺癌回顾性研究证实 • 114 pats received cryobrachytherapy (n=36, 3 cycles of freeze thaw + I125 seeds placement) or immunotherapy (n=17, DC CIK cells injected) or both (n=31)
114患者接受冷冻粒子种植近距离放疗（冷冻解冻36.3周期+1125粒子种植）或免疫治疗（N=17，DC-CIK细胞注射）或两者（N=31）
  免疫治疗在乳腺癌中的作用 Role of immunotherapy in breast cancer
• Breast cancer is considered as a low immunegic tumor demonstrating low TIL density and strong mechanisms of immunogenic resistance
乳腺癌被认为是一个低免疫低免疫源性肿瘤显示低肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)密度和强大的免疫原性阻力的机制 • BUT recently– TILs infiltration have demonstrated 但最近 肿瘤浸润淋巴细胞(tumor infiltrating lymphocyte,TIL)浸润证明存在 • To be present with a high density in 20% only of breast cancer particularly in TNBC and HER 2 + 高密度只存在于20%的乳腺癌，特别是三阴性乳腺癌(triple negative breast cancer,TNBC)和HER2+阳性 • To be correlated to response to neoadjuvant chemo (NACT) （免疫治疗）与新辅助化疗(NACT)反应相关 • Is correlated with survival when measured post NACT （免疫治疗）与新辅助化疗（NACT）后的生存相关    
• Study design:实验设计
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PBCMC by flow cytometry:
Increased frequency of activated T cells (ICOS hi) and proliferative T cells (Ki67+) in the combination group Both for CD 4 T reg and CD 8. cytotoxic T cells
流式细胞术检测PBCMC(外周血单个核细胞计数）：
联合组CD4Treg和CD8细胞毒性T细胞的活化T细胞(ICOShi)和增殖T细胞(Ki67+)频率均增加。 |
TILS by flow cytometry on mastentomy specimen.
通过流式细胞计数检测TILS。
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血清细胞动力学对治疗的反应 Serum Cytokine response to therapy
Noc changes until day 30 post mastectomy
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Heat map of fold increase vs baseline: – IFN gamma changes are more frequent in the combination as well IL 2 (activation of LT Helper) and IL 12 ( differenciation in LT helper)
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Lessons and limitations of the study
• No statitical differences between groups but more favorable signals in the combination therapy than in stand alone treatments
• ICOShi is a CD28 CTLA4 surface molecule upregulated after T Cell activation is a biomarker of CTLA 4 treatment
– Highly expressed in the combo and in the proliferative T cells
– Strong signal in favor of the combination therapy
– Cryotherapy in a complete ablation strategy does not seem very efficient for triggering immune response as a stand alone treatment
• Further studies are needed
– Best cryo protocol
– Intra tumoral vs systemic treatment of CTLA 4 in this setting