CHINA癌症免疫治疗
Preface
i. 这是本公号第37篇。
ii. 接受比特币、以太坊打赏
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1、PD-1/PD-L1
2、PD-1之. CRISPR基因治疗
3、寻找可能获益人群
i. PD-L1检测
Roche Diagnostics. VENTANA PD-L1 (SP263) Assay.
Dako North America, Inc. PD-L1 IHC 22C3 pharmDx.
评：
i、VENTANA PD-L1 (SP263) Assay评估肿瘤微环境PD-L1表达水平和Dako PD-L1 IHC 22C3 pharmDx评估肿瘤细胞PD-L1表达水平有所差异。
ii、科学性上讲，似乎评估肿瘤微环境PD-L1表达水平更有探索价值。
iii、T细胞的命运并不是由抗原决定，抗原只能启动T细胞，但是不能决定它的方向。
附8月文献：模型小鼠实验中，PD-1/PD-L1抗体疗效深受肿瘤微环境影响。
i、CMT167原位肿瘤PD-阳性T细胞丰度 > 皮下CMT167肿瘤，PD-1/PD-L1免疫治疗对CMT167原位肿瘤抑制率达95%，对皮下CMT167肿瘤抑制率30%，LLC的原位肿瘤的抑制率为35%。
ii、沉默CMT167 肿瘤细胞PD-L1表达，原位肿瘤依然缩小且对PD-L1免疫治疗仍敏感。
iii、CMT167肿瘤细胞（PD-L1+）植入PD-L1阴性小鼠，阻断原位肿瘤进展。
Reference：Li, Howard Y., et al. The Tumor Microenvironment Regulates Sensitivity of Murine Lung Tumors to PD-1/PD-L1 Antibody Blockade. Cancer Immunology Research 5.9 (2017): 767-777.
ii. 微卫星不稳定 MMR & MSI-H
除了前不久新闻爆炒的用于Keytruda适应症（既往已接受治疗的晚期高微卫星不稳定性癌症患者的补充生物制品）之外，微卫星不稳定检测的另外一个重要临床意义是用于结直肠癌分子分型和治疗方案决策。
除Ketruda之外，NCCN指南也有推荐PD-1单抗Nivolumab用于dMMR/MSI-H结直肠癌晚期治疗。
[1] Hause, Ronald J., et al. "Classification and characterization of microsatellite instability across 18 cancer types." Nat Med 22.11 (2016): 1342-1350.
[2] Le, Dung T., et al. "Mismatch-repair deficiency predicts response of solid tumors to PD-1 blockade." Science (2017): eaan6733.
iii. CD8 T细胞：预测&监测
评：
i、CD8+ T细胞检测，其实有肿瘤微环境中免疫杀手到位确认的意思。
ii、肿瘤微环境中CD8+ T细胞PD-1表达水平提升也会促进肿瘤增值活性。
Combinatorial CD8+ and PD-L1+ cell densities correlate with response and improved survival in non-small cell lung cancer (NSCLC) patients treated with durvalumab
Sonja Althammer1, Keith Steele2, Marlon Rebelatto2, Tze Heng Tan1,Tobias Wiestler1, Guenter Schmidt1, Brandon Higgs2, Xia Li2, Li Shi2, Xiaoping Jin2, Joyce Antal2, Ashok Gupta2, Koustubh Ranade2, Gerd Binning1
Results
Patients with high pretreatment CD8+ and PD-L1+ densities (prevalence = 36%) had better ORR, OS, and PFS compared to those with low CD8+ and PD-L1+ densities (Fig. 1), as well as high PD-L1 expression alone.
Conclusions
Automated image analysis of CD8+ and PD-L1+ cell densities in baseline tumor biopsies may identify patients with improved outcomes to durvalumab.
Trial Registration:ClinicalTrials.gov identifier NCT01693562.
Dual Positive PD-L1 and CD8+ TIL Represents a Predominant Subtype in NSCLC and Correlates with Augmented Immunogenicity
Si-Yang Liu1, Zhong-Yi Dong2, Wen-Zhao Zhong3, Si-Pei Wu1, Zhi Xie2, Hai-Yan Tu4, Yi Long Wu1
Results
288 cases with stage I-IIIA NSCLC were evalu- ated for PD-L1 and CD8+ TIL staining. Dual positive PD-L1 and CD8 (PD-L1+/CD8+) represents a predominant sub- type in NSCLC, accounting for 36.5% (105/288), followed by PD-L1-/CD8- (24.3%, 70/288), PD-L1-/CD8+ (26.0%, 75/288) and PD-L1+/CD8- (13.2%, 38/288). Survival analysis of DFS (p1⁄40.031) and OS (p1⁄40.002) showed a significant difference between four subgroups. Further- more, we analyzed the correlation between expression types of PDL1/CD8 and mutation burden and angtigen presentation. We can identified dual positive PD-L1 and CD8 was significant with increased mutation burden (p<0.001), high frequency of mismatch repair (MMR) related gene mutation. More interestingly, tumor with dual positive PD-L1 and CD8 manifested a remarkable activated angtigen presentation and T cell receptor signature compared with other subgroups.
Conclusion
Dual positive PD-L1 and CD8 was identified as a predominant subtype in NSCLC and correlates with increased immunogenicity. These findings provide the evidence that combined analysis of PD-L1 and CD8 in NSCLC may be a promising way to predict PD-1 blockade immunotherapy.
iv. 肿瘤突变负荷 Tumor Mutation Burden, TMB
评：
借用大师说法，是回顾性研究，如果前瞻性研究也是这样漂亮的数据就牛逼了。
Foundation Medicine blood test for tumor mutational burden to be used by Roche as companion diagnostic test in late-stage lung cancer study
|By: Douglas W. House
4、CAR-T
国内登记开展CAR-T临床研究项目已超过100项，不出任何意外，主要以血液肿瘤为主。
主流抗原以CD19居多，毕竟Kymriah（CTL019）治愈了Emily，今年8月底FDA也获批了。
CAR-T疗法靶向抗原还是以前人的研究结果为主，抗原也多是人体正常细胞抗原。
如下图所示，CD19其实是人体全B细胞抗原，而不是肿瘤特异性抗原。而CD19-CAR-T治疗事实上也是以牺牲正常B细胞为基础发展而来。
国内主要公司：
南京传奇生物科技，抗BCMA CAR-T细胞（LCAR-B38M）。
西比曼生物科技，3个II期临床 (CBM-C30.1，CD30;CBM-EGFR.1, EGFR; CBM-C19.1,CD19), 与解放军总医院（301医院）合作。
博生吉，3个II期临床 (MUC1 CAR T, MUC1; CAR-pNK; PCAR-019, CD19), CAR-T技术、CAR-NK技术、CTL技术、DC-CTL技术。
其它如，复星医药、药明巨诺、科济生物、恒瑞源正生物、吉凯基因、恒润达生、上海斯丹赛...
Jaffe, Elaine Sarkin, et al. Hematopathology 2nd Edition.
PS. CRISPR应用场景
1、工农业
Calyxt，用于农作物育种，如高含油量大豆、高纤维小麦、高抗旱大豆。
Recombinetics，畜牧业、家禽、水产，如不长牛角的奶牛。
eGenesis，敲除猪器官内源性逆转录病毒PERV序列，提供器官移植供体猪种。
美孚与SystemGenomics合作，利用测序、CRISPR技术，提升海藻脂肪转化率，用于燃料生产。
农业巨头孟山都也拿了Broad Institute农业领域应用CRISPR-Cpf1系统专利授权。
巴斯夫则拿了Broad Institute农业、工业微生物中的应用专利授权许可。
2、单基因相关疾病
HIV病毒感染、先天性脂蛋白分解病、莱伯先天性黑盲病，等。
3、肿瘤
动物疾病模型，中科院李劲松教授将CRISPR应用于孤雌细胞研究，构建了小鼠孤雌单倍体干细胞库。
肿瘤新靶点发现及机制研究，参看【CRISPR & AI 筛选药物靶点】。
PD-1基因治疗，参看上文。
CAR-T免疫治疗。
配图仅供娱乐 | 2013年秋黄不接时
祝，
君安