细胞免疫应答的时相
 

体液免疫应答时相
 

肿瘤免疫编辑 Cancer immunoediting

三个阶段：

免疫监视（elimination ）

免疫平衡（equilibrium ）

免疫逃逸（escape）

也称为肿瘤免疫编辑的3个“E”。

佐剂 adjuvants

● cytokines: GM-CSF, IL-12

● Microbes and microbial derivatives: BCG, CpG, Detox, MPL, poly I:C

● Mineral salts: Alum

● Oil emulsions or surfacants: AS02, MF59, Montanide ISA-51, QS21

● Particulates: AS04, polylactide co-glycolide, virosomes

● Viral vector: Adenovirus, vaccinia, fowlpox

肿瘤疫苗种类：

● 肿瘤抗原疫苗：抗原肽疫苗，重组蛋白疫苗,DNA疫苗

● 树突状细胞疫苗：

● 基因工程瘤苗：肿瘤细胞转染CKs或CD80等

肿瘤抗原疫苗：

● 表位肽疫苗：9-10aa，临床成功率低

● 长肽疫苗：~25-50aa
HPV16 E6, E7: 20例，全部恢复，9例病毒清除
P53长肽疫苗用于复发的卵巢癌患者，可检测到特异免疫应答，但无明显临床效果

● 蛋白疫苗：产生的免疫应答强

● DNA 疫苗：

HSP-peptide complexes

gp96-peptide or HSP70-peptide complex from tumor specimens
DNA vaccine
 

基因工程瘤细胞疫苗
肿瘤细胞转染共刺激分子或细胞因子：
 

Therapeutic vaccines act via DC cells to generate protective CD8+ T cell immunity
DC 疫苗
 

Dendritic cells play a central role in vaccination
CD4+T: IFN γ/IL-21 help CD8+T cell expansion and differentiation
Tregs：suppress DCs via IL-10 and regulate the production of chemokines.
CD4+T：provide DC maturation signals via CD40
如何克服免疫抑制：调节免疫检查点(checkpoint)
 

Immune dysfunction inhibiting vaccine efficacy in cancer
Vaccine antigen specific T-cell pool is mostly exhausted

T-cells activated by vaccines are inhibited in the tumor microenvironment

Key issues in active immunotherapy in clinical practice

● Use of suitable adjuvants
optimal combination of antigens, adjuvants and delivery vehicles
prime-boost strategies

● Multimodality treatment
active immunothrapy in combination with other treatments

● Patient selection
early-stage or indolent disease, tumor growth is controlled

detailed information of immune functions (tumor specific T cells and autoantibodies as well as immune cell subpopulations and chemokines in the circulation and tumor microenvironments)
Combination of active immunotherapy with other treatments

● combination with debulking surgery

● combination with radiotherapy

● combination with chemotheray

● combination with signal transduction inhibitors (rapamycin)

● combination with adoptive T-cell transfer

● combination with cytokines

● combination with monoclonal antibody antagonists of immune checkpoints (anti-CTLA-4, anti-PD-1)

● combination with small molecule inhibotors of tumor-mediated immunosuppression

Roadmap to the development of predictive biomarkers for active immunotherapy

肿瘤抗原作为疫苗的条件：

● 在正常组织不表达或局限表达于某些组织。

● 在肿瘤组织广泛表达。

● 具有免疫原性，可诱导机体产生免疫应答。

● 在肿瘤细胞发生、发展中起重要作用。