化疗联合免疫治疗新模式(任+军+20120707)

High expression of Hsp90 is associated with poor prognosis
IHC PROTEIN EXPRESSION (AQUA)
In situ ductal carcinoma with moderate expression of Hsp90 (×200) From Zagouri et al BMC Cancer 2010
化疗药物的免疫调节作用机制
提高肿瘤细胞的免疫原性 Chemotherapy 对机体免疫细胞的作用
Tumor apo百度文库tosis
CRT HSP HMGB1
Lymphopenia T cell proliferation (Ag specificity) “re-booting” immune system
US FDA approvals and PIII studies
Drug Provenge Ipilimumab(Yervoy) Astuprotimut-r Belagenpumatucel-L BiovaxlD Emepepimut-S (Stimuvax) Developer Dendreon BMS GSK NovaRx Biovest Merck Serono Indication CRPC Melanoma NSCLC; Melanoma NSCLC Follicular lymphoma NSCLC Status Approved(April2010) Approved(March2011) Phase III Phase III Phase III Phase III
肿瘤免疫治疗的机制和途径
Nonspecific : 1970’s Specific: 2000’s-
• • • •
Cytokines Interferon Bacteria products Tumor necrosis factors • Natural products
APP: Antigen processing and presentation; CK: Cytokines; GC: Granulocyte; LC: Lymphocyte; MP: Macrophage; TC: Tumor cell; TLR: Toll-like receptor DCK: direct cell killing; TCR:T-cell receptors
• PS 0-1, HLA-A2+, CEA +, previously-treated PC • Arm A 10 μg • Arm B 100 μg • Arm C 1000 μg • CEA-vac was given Q 2 weeks until disease progression (amended 4/09 to a 24 dose maximum). • 19 pts randomized to Arms A/B/C 5/8/6 are evaluable for toxicity • 14 pts (5/5/4) who received at least 3 doses of CEA-vac are evaluable for the primary immunologic endpoint
免疫效应细胞 B cells CTL ……
免疫抑制细胞 调节性T细胞（Treg) 髓样来源的抑制性细胞(MDSC) 抑制性T细胞（Ts） ……
免疫抑制因子 TGF-b，IL-10，VEGF ……
(From Hanahan and Weinberg, Cell 2011)
RECEPTORS MEDIATING SIGNALING ARE “CLIENTS” THAT ARE OFTEN “CHAPERONED” BY SPECIFIC PROTEINS: HEAT SHOCK PROTEIN 90 (Hsp90)
Hsp90 Expression in Breast Cancers by protein expression analysis (AQUA) From Pick et al Cancer Research 2007
GENE EXPRESSION OF Hsp90 IN BREAST CANCER
No of patients
Low 80% (n=851)
High 20% (n=356)
(From Cheng Q, et. al. unpublished)
化疗药物的免疫调节作用
Chemotherapy Drug Doxorubicin Doxorubicin Oxaliplatin High dose chemotherapy Cyclophosphamide Cisplatin Paclitaxel Gemcitabine Gemcitabine 5-fluorouracil Cyclophosphamide Paclitaxel Cyclophosphamide Paclitaxel Doxorubicin Immunologic Process Antigen uptake Antigen processing Homeostatic proliferation Mechanism Cell surface calreticulin HMGB1 release IL-7, IL-15, IL-21; inhibition of Treg inhibition of Treg
Histograms of HSP90 expression in 4010 breast cancer pateints 700 600 500 400 300 200 100 0 HSP90AA1 expression
Over_all survival of HSP90AA1 in 1027 breast cancer samples Percent survival
Trigger DC maturation
T cell immunity
DC↑ + Regulatory T Cell (Treg)↓ + Myeloid-Derived Suppressor Cells (MDSC) ↓
Active immune system
Cancer J. 2010 ; 16(4): 295–303.
PC: pancreatic adenocarcinoma. J Clin Oncol 30, 2012 (suppl; abstr 2561)
A randomized pilot phase I study of modified CEA peptide (CAP1-6D)/montanide/GM-CSF-vaccine (CEA-vac) in pts with PC
Regulatory cell function
Regulatory cell function Immunologic skew Antigen presentation
Reduced MDSC numbers Promotes T helper type 1 immunity Augment DC function
A randomized pilot phase I study of modified CEA peptide (CAP1-6D)/montanide/GM-CSF-vaccine (CEA-vac) in pts with PC
PS 0-1, HLA-A2+, CEA +, previously-treated PC
作用机 制不同 起效时 间 化疗的 免疫抑制 作用 作用持 续时间 清除肿 瘤干细胞
免疫治疗： 清除化疗耐药细胞 起效慢 作用持续时间长 清除肿瘤干细胞
肿瘤免疫抑制细胞与效应细胞 Active
Memory cells
DC1
APC
Signal 1 Signal 2
T 细胞
CD4+
Effector
CEA-vac q2w Arm A Arm B Arm C 10ug 100ug 1000ug 19 pts evaluable for toxicity 5 8 6 14 pts received ≥3 doses, evaluable for the primary immunologic endpoint 5 5 4
n 1028 30
Vaccine KLH (n=505) KLH-STn (n=523) IMP321 (LAG-3Ig fusion protein)
Drug CY 300 mg/m2
Immunologic Outcome NR, no clinical difference
Phase I
28
GM-CSF-secreting HER-2+ breast tumor cells
Immunotherapy Chemotherapy
Target therapy
内分泌
放疗
Chemotherapy combined with immunotherapy. Chemotherapy kill or slow the growth of cancer cells; Immunotherapy stimulate or restore the ability of the immune system to fight cancer.
化疗联合免疫治疗新模式 ----肿瘤治疗的新思考
首都医科大学肿瘤医学院 首都医科大学附属世纪坛医院肿瘤中心 美国杜克大学医学中心 教授 （Faculty,Duke Univ Med Ctr) 任军 2012-07-07
肿瘤治疗观念的变迁
Chemoimmunotherapy -----化疗联合免疫治疗
KLH=keyhole limpet hemocyanin; STn=clustered carbohydrate antigens; CY=cyclophosphamide; NR=not reported; DOX=doxorubicin ORR=objective response rate
Journal of Translational Medicine 2010, 8:71
Percent survival Survival of HSP90AA1 in 198 TNBC 100 80 60 40 20 0 0 P=0.0052 2 4 6 8 10 12 14 Time(year)
Low80 (n=173) High20 (n=25)
100 80 60 40 20 0 0 P=0.0035 2 4 6 8 10 12 14 Time(year)
Expert Opin. Biol. Ther. (2012) 12(4):479-490
“化疗+免疫”治疗模式的优势
1979年，美国M.D. Anderson癌症中心 FAC vs. FAC+BCG 转移性乳腺癌 n=105 PFS 9m vs. 14m, OS 15m vs. 24m
Cancer J. 2010 ; 16(4): 295–303.
HMGB1：高速泳动球蛋白盒B1（high-mobility globulin box B1）
Clinical Trials of Chemoimmunotherapy in metastatic breast cancer
Phase Phase III Phase I/II
PTX 80 mg/m2 at D1, D8 and D15, for ORR of 50% 6 cycles CY 0, 200, 250, 350 mg/m2 increased HER-2DOX 0, 15, 25, 35 specific mg/m2 immunity with CY (factorial design of 200 mg/m2 various plus DOX 35 mg/m2 dose combinations)
HEAT SHOCK PROTEIN 90 (Hsp90) has over 200 clients, and is involved in many cellular processes, modulated by co‐chaperones and post‐translational modifications