Dr. & Prof. Liqun Jia Dr. Jan FagerbergOncology Department of Integrative Medicine Chief Medical OfficerChina-Japan Friendship Hospital, Beijing, China SOTIO中日友好医院 中西医结合肿瘤科 SOTIO首席医学事务官贾立群

Clinical Study of Constitution Selected TCM Injection with DC Immunotherapy Treating

NSCLC and CRPC基于中医体质优选中药联合树突状细胞免疫治疗非小细胞肺癌和去势抵抗性前列腺癌的临床研究

Combination Application with DC ImmunotherapyDC免疫疗法的联合应用研究

• Nature: Combination of Tetanus toxoid and DC significantly prolongs glioblastoma patients’ survival (2015.3.11)

Nature：破伤风毒素联合DC免疫疗法显著延长胶质母细胞瘤患者生存（2015.3.11）

• 12 patients are enrolled, OS：11.6 movs 51-101 mo, 1 patient’s PFS has been 8 yr

入组12例患者，两组OS：11.6月 vs 51-101月，其中1例已维持8年无进展生存

Mitchell DA, Batich KA, Gunn MD, et al. Tetanus toxoid and CCL3 improve dendritic cell vaccines in mice and glioblastoma patients[J]. Nature. 2015 Mar 19;519(7543):366-9.

Combination Synergy联合 增效

Tetanus Toxoid + DC = Synergy破伤风毒素+DC=增效

Clinical Study of Constitution Selected TCM Injection with DC Immunotherapy Treating NSCLC and CRPC

基于中医体质优选中药联合树突状细胞免疫治疗非小细胞肺癌和去势抵抗性前列腺癌的临床研究

TCM+DC=中医+DC=

OS

Qi Deficiency: Fatigue气虚体质：疲乏

Qi Deficiency 气虚Normal 正常

Blood Stasis: Tarnish血瘀体质：晦暗

Blood Stasis 血瘀Normal 正常Yang Deficiency: Fear of Cold阳虚体质：畏寒

Normal YangDeficiency

NormalYangDeficiency

Yin Deficiency: Dry阴虚体质：干燥

Yin Deficiency 阴虚

Constitution Differences

中医体质 Normal 正常

《中医体质分类及判定》，中华中医药学会体质分会，2009 阳虚 正常 阳虚 正常

NSCLC with Qi Deficiency 气虚的NSCLC

Huangqi黄芪Astragali

• Promote DC’s differentiation, significantly increase the expression of surface markers CDla CD80 and CD86 可促进DC细胞分化，明显增加表面标志物CDla、CD80和CD86的表达

• DCs are induced to stimulate allogeneic T lymphocyte proliferation, significantly increase the levels of IL-12 and IFN-γ 诱导成熟的DC能刺激同种异体T淋巴细胞增殖，显著增加共培养上清IL-12、IFN-γ的水平

• DC vaccine induced could enhance DC’s antigen presenting ability, effectively activate CTL, increase IL-12 and TNF-α, enhance the anti-tumor function, and prolong tumor-burdened mice’s life诱导的树突状细胞肿瘤疫苗可促进DC细胞的抗原递呈能力，有效活化CTL，促进细胞因子IL-12、TNF-α，增强机体抗肿瘤功能，延长荷瘤小鼠生命

荆雪宁,邱波,王金凤,等. 黄芪多糖诱导成熟的树突状细胞肿瘤疫苗体外抗肿瘤作用的实验研究[J]. 中国中西医结合杂志,2014,09:1103-1107.邱波,荆雪宁,武继彪,等. 黄芪多糖诱导的树突状细胞疫苗对S180荷瘤小鼠抗肿瘤作用研究[J]. 南京中医药大学学报,2015,01:44-47.

• Clinical feature: Cough and expectoration, blood-stained sputum, mentally fatigued, weak breath and lazy to talk, pale tongue andwhite tongue fur, weak pulse临床表现：咳嗽咳痰，痰中带血，神疲乏力，少气懒言，自汗眩晕，舌淡苔白，脉弱

• Differentiation of TCM: Qi Deficiency Constitution (account for 74.16% of NSCLC)中医辨证：气虚体质（占总NSCLC的74.16%）

• Design: Tonifying qi & strengthening the body resistance+DC+Chemo vs DC+ Chemo

研究设计：益气扶正+DC+化疗 vs DC+化疗

• Selected TCM: Huangqi Zhusheye (HQ) 选择中药：黄芪注射液（HQ）

• Clinical feature: dribbling urination, dysuria, hematuresis, perineal pain, tireness, soreness and weakness of waist and knees临床表现：小便淋沥，排尿困难，血尿，会阴疼痛，神疲倦怠，腰膝酸软

• Huang di's Canon of Medicine: For a sixty-four aged male, five internal organs decline, bones and muscles are stiff, hormones are exhausted 黄帝内经：男子八八（64岁），“五脏皆衰，筋骨解堕，天癸尽矣”

• Differentiation of TCM: Yang Deficiency Constitution (account for 59.29% of PCa)中医辨证：阳虚体质（占总PC的59.29%）

• Design: Warming yang & strengthening the body resistance+DC vs DC研究设计：温阳扶正+DC vs DC• Selected TCM: Shenfu Zhusheye (SF) 选择中药：参附注射液（SF）

CRPC with Yang Deficiency 阳虚的CRPC

Hongshen红参Ginseng

Fupian附片Aconiti

• GM-CSF and IL-4 are combined to induce HL-60 to be mature DCs, to increase DC’s antigen presenting ability, to promote the secretion of INF-γ, could promote maturation and suppress proliferation 可以联合GM-CSF和IL-4诱导HL-60细胞成为成熟的DCs，使其抗原递呈功能明显增强，分泌 INF-γ，并表现促进成熟和抑制增殖的双向调节作用

• Improve and adjust post-chemotherapy leukemia patients’ immune function, significantly increase CD4 and D4/CD8, decrease IL-6 and TNF-α 改善、调节急性白血病化疗患者的免疫功能，明显提高 CD4、CD4/CD8，降低血清 IL-6 和 TNF-α水平

魏影非,杜惠兰,王素云,等. 参附注射液配合化疗治疗急性白血病疗效及对细胞免疫、血清IL-6 和 TNF-α 水平的影响[J]. 中国中西医结合杂志, 2003, 23（4）:258~260任莉莉,问明,李淑青等. 参附注射液联合细胞因子对急性髓性白血病HL-60细胞来源的树突状细胞诱导生成及功能的影响[J]. 河北医药,2013,06:818-821.

DCVAC/PCa • Patient visits leukapheretic center where his blood is used to…患者抵达采血中心进行白细胞单采…

• … separate monocytes and grow immature DCs… 分离单核细胞并使其分化成为未成熟树突状细胞

• Tumor cell line1 is prepared and killed by immunogenic death 准备肿瘤细胞株并使其发生免疫原性死亡

• Immature DCs are mixed with killed tumor cells将未成熟树突状细胞与死亡的肿瘤细胞共培养

• Mature DCs are prepared制备好成熟树突状细胞

• ~18 doses of DCVAC/Pca are produced and frozen in liquid nitrogen生产出约18剂DCVAC/Pca 并在液氮中冻存

• Patient receives vaccine on an ongoing basis (1 shot per month) 患者按计划进行疫苗注射（每月1剂）

1

2

3

4

5

6

7All processes need state of the art scheduling and logistics

所有的流程均需要妥善的计划和物流调度

1 Acquired from ATTC

3

4

• Randomized, controlled, multicenter study. Sixty Ⅲ-IV NSCLC patients and 60 CRPC patients are included

采用多中心，随机、对照的研究方法，纳入60例Ⅲ-IV期NSCLC 和60例CRPC患者

• Chinese Patent Injection are selected as immunity synergist, according to patients’constitution

根据中医体质证型，选择已经上市中成药注射液作为免疫增效剂

• Chinese Patent Injection is combined with DC injection, to evaluate the safety and efficiency of individualized TCM intervention, and compare the immune function, quality of life, and TCM syndrome before and after the treatments

在DC细胞回输治疗中联合相应中成药注射液进行干预，评价优选个体化中药干预的有效性和安全性，及治疗前后患者免疫功能、生活质量和中医证候改善

Study Content 研究内容

TCM*14days

DC

IV NSCLC, n=60 IV期NSCLC60例

Protocol – NSCLC 研究方案-NSCLC

HQ+DC+CT DC+CT

EfficiencyOS/PFS,

ORR/DCR, 1-year

survival

有效性

OS/PFSORR/DCR1年生存率

Immune FunctionT cell phenotype and functional

subset, T cell clone distribution

免疫功能

T细胞表型及功能亚群

T细胞克隆分布

Quality of Life

FACT-L

生活质量

FACT-L

Evaluation of Syndromes

Tongue diagnosis, Chinese medicine symptom score

中医证候评价

舌诊中医证候评分

SafetyClinical feature,

Physical, lab, auxiliary, and

other examinations

安全性

临床表现体格检查

实验室检查辅助检查

Protocol – CRPC 研究方案-CRPCCRPC, n=60 去势抵抗性前列腺癌60例

SF+DC DC

EfficiencyPSAPFS

有效性

PSAPFS

Immune FunctionT cell phenotype and functional

subset, T cell clone distribution

免疫功能

T细胞表型及功能亚群

T细胞克隆分布

Quality of Life

FACT-P

生活质量

FACT-P

Evaluation of Syndromes

Tongue diagnosis, Chinese medicine symptom score

中医证候评价

舌诊中医证候评分

SafetyClinical feature, Physical, lab, auxiliary, and

other examinations

安全性

临床表现体格检查

实验室检查辅助检查

Previous Studies Results 前期研究基础Ten NSCLC patients and 6 CRPC patients are included前期课题已入组完成NSCLC患者10例+CRPC患者6例

• General Information: female 8, male 8; median aged 69 (32-84)一般资料：女性8例、男性8例；中位年龄69岁（32-84岁）

• DC injections: 46 times 回输次数：46次• AR: 2 cases (low-grade fever and headache 2 days after injection)

不良反应：2例（注射第2天低热、头痛）

• PR for lung squamous cell carcinoma after treatment: 肺鳞癌治疗后PR：

• PSA changes for PCa: 前列腺癌PSA变化：

2015-3-18 2015-4-28

Vltava River 伏尔塔瓦河 Yellow River 黄河