医学免疫学课件：Recent advances in Breast cancer vaccines

1、Recent advances in Breast cancer vaccinesMolecular types of breast cancerLuminal A: ER+ or PR-, HER-, FOXA1+ ( good prognosis)Luminal B:ER+ or PR+, HER+TNBC: ER-, PR-, HER2-HER+ER-, PR-, HER2+Mechanisms of breast cancerabsence of an adequate immune response up-regulation of inhibitory immune checkpo

2、ints LPBC and TIL:TNBC: No resultsHER2+Good PrognosisLack of large phase III trials Mechanisms of breast cancerFigure 2 Relevant immune checkpoints in breast cancer1TAAsDefinition: self-antigens predominantly on BCCsFunction: Facilitate CTL responsesFigure 1 Immune system functions and components re

3、levant to breast cancer therapy2Breast cancer vaccinesTumor cell vaccinesPeptide-based vaccines DC vaccinesDNA vaccinesTumor cell vaccines irradiated, freshly isolated primary tumor cells oil-based emulsion GM-CSF-transduced Strengths:Elicit a response to wide spectrum of antigensNot HLA-restrictedW

4、eaknesses:Difficult to monitor responseRisk of toxicities and autoimmunityRequires cell manipulation to be immunogenicPeptide-based vaccines using antigenic epitopes derived from TAAs.Figure 1 Types of TAAs345TargetsDescriptionHuman epithelialgrowth factorreceptor 2(HER2)E75GP2AE37Growth factor rece

5、ptor belonging to human epithelial growth factor receptor family Overexpressed in 20%30% of breast cancer cells, correlates with adverse prognosisMUC-1Membrane glycoprotein involved in immunologic and cell signaling functions Overexpressed in 70% of breast cancersCancer testis antigens(NY-eso-1, MAG

6、E,BAGE, and GAGE)Proteins expressed in normal germ cells of the testis and embryonic ovaries and in certain types of cancerhTERTComponent of the telomerase complex, a ribonucleoprotein that maintain chromosome integrity during cell proliferation and divisionSurvivininhibitor of apoptosis expressed d

7、uring fetaldevelopment.Carcinoembryonic AntigenGlycoprotein involved in cell adhesion, normally expressed during fetal developmentNY-BR-1one of the most over-expressed breast cancer-specific antigens found to date, especially in ER+ breast cancerWT1overexpressed in leukemia and a variety of solid tu

8、mors. Necessary for the development of the kidneys and gonads.P53Combination of CD4+ T-Helper Cell(HLA class II) Epitopes with HLA Class I Epitopes in Breast Cancer VaccinesEpitope Spreading by Single TAA Peptide VaccinesPeptide vaccinesAdvantagesGenerated with high purity Low costDisadvantagesweakl

9、y immunogenic for eradicating large tumors. restricted by HLA typeDC vaccinesuses mature DCs MHC class I, II and a host of co-stimulatory ligands.DEC205poly-inosinic:polycytidylic acid(poly I: C)Steinman groups studiesDC vaccinesFigure 2 ADM-induced apoptotic MCF-7 cells induce iDC maturation6DC vac

10、cinesAdvantagesMore beneficialDisadvantages too complex to generate reproducibly must be customized for each patient intra-nodal injection DNA vaccines Delivery: nakedVirusesNew technologies: nanoparticles & liposome preparatonspox viruses metastatic breast cancer patients. focuses too much on respo

11、nding to the viral antigens mammaglobin-ASafe no significant adverse events SummaryLimitationsFuture perspectivesResponse with no impact on tumor growtheliciting a wide response, involving multiple immune effectors immuno-escaping mechanisms block modulatory checkpoints Insuffient for patients with

12、large tumor burdencombining vaccine with established drugs TNBC: novel strategiesReference1Loibl, Sibylle, and Jenny Furlanetto. Targeting the Immune System in Breast Cancer: Hype or Hope?: TILs and Newer Immune-Based Therapies Being Evaluated for HER2+ and TNBC.Current Breast Cancer Reports7.4 (201

13、5): 203-209. 2 Criscitiello, Carmen, et al. Immune approaches to the treatment of breast cancer, around the corner?.Breast Cancer Research16.1 (2014): 204.3Harao, Michiko, Elizabeth A. Mittendorf, and Laszlo G. Radvanyi. Peptide-Based Vaccination and Induction of CD8+ T-Cell Responses Against Tumor

14、Antigens in Breast Cancer.BioDrugs29.1 (2015): 15-30. 4Li, Lijin, et al. Developing a clinical development paradigm for translation of a mammaglobin-A DNA vaccine.Immunotherapy7.7 (2015): 709-711.5Stanton, Sasha E., and Mary L. Disis. Designing vaccines to prevent breast cancer recurrence or invasive disease.Immunotherapy7.2 (2015): 69.6. Zheng, Jin, e