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Immuno and Epigenetic Therapies

Immuno and Epigenetic Therapies. Xiaole Shirley Liu STAT115, STAT215, BIO298, BIST520. Cancer Immunology. Would tumor grow in another individual?. Effector Lympocytes. Lymphocytes express highly specific ANTIGEN RECEPTORS on their surface

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Immuno and Epigenetic Therapies

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  1. Immuno andEpigenetic Therapies Xiaole Shirley Liu STAT115, STAT215, BIO298, BIST520

  2. Cancer Immunology • Would tumor grow in another individual?

  3. Effector Lympocytes • Lymphocytes express highly specific ANTIGEN RECEPTORS on their surface • Lymphocytes are highly specific for a given structural motif • Usually CD8+ cells which kill target cells by recognizing foreign peptide-MHC molecules on the target cell membrane.

  4. Tumors • Cancer cells must express ANTIGENS (foreign particles) recognizable and accessible to the immune system. - Antigenicity • The immune system must in turn be able to mount a response against cells bearing such antigens • Tumors possess a varying degree of Immune “Antigenicity” that is unique to each tumor and thus be rejected by immunocompetent hosts.

  5. Cytokines • Low molecular weight protein mediators involved in cell growth, inflammation, immunity, differentiation and repair • Production triggered by presence of foreign particles • Interleukins (ex. IL-2) and interferons • Acts as a potent immunomodulator and antitumor element, but might have extensive multiorgan toxicity

  6. Active Immonotherapy • High dose IL-2 (FDA approved for kidney cancer and melanoma) • Boost overall immune cells inside the patient body

  7. Using Antibodies to Boost Immune Systems • Anti CTLA-4 and anti-PD1 antibodies can allow T-cell activation

  8. Adoptive Immunotherapy • Isolate tumor-infiltrating lymphocytes (TILs) • Expand their number artificially in cell culture • Infuse TIL back into the bloodstream, recognize and destroy the tumor cells

  9. Effectiveness of ImmunoTherapy

  10. CAR • Chimeric antigen receptors: proteins that allow the T cells to recognize specific antigen on tumors • Side effects: rapid and massive release of cytokines into the bloodstream

  11. Find mutations from exome sequencing • Use bioinformatics program to find mutations that might be immunogenic • Create vectors expressing the small peptides containing the mutations • Co-culture to activate TIL

  12. Personalized ImmunoTherapy • Great for melanoma, lung and colon cancer • Immunotherapy specific to each patients’ tumor mutations

  13. Bioinformatics? • Which mutations are expressed? • Which proteins might be on the cell membrane? • Which peptides are immunogenetic? • Cancer vaccine?

  14. Epigenetic Drugs • HDAC inhibitor to delay drug resistance • Minimum 5-aza (DNA demethylation)

  15. Treat Cell Lines

  16. Directly Treating Mice

  17. Effect of 5-aza • Minimum dosage and toxicity, well tolerated • Activate suppressed immune genes • Can use DNA methylation status at these immune genes to predict patient response • Small % of patients directly cured. • Others re-sensitized for chemotherapy • Can be used with other drugs?

  18. Summary • Immunotherapy: a living drug! • Active vs adoptive immunotherapy • Personalized immunotherapy: bioinformatics? • Epigenetic therapy: 5-aza immune response

  19. Final Review • Programming: python and R • Statistics: Tukey bi-weight, median polish, qnorm, FDR, PCA, SVM, HMM, EM / Gibbs • Technologies: microarrays (RMA, LIMMA, GSEA), NGS for DNA-seq (Bowtie, GATK), RNA-seq (Cufflinks), ChIP/DNase-seq (MACS), GWAS (plink), cell line drug and sh/sgRNA screens • Biological problems: transcriptional and epigenetic gene regulation, disease susceptibility, diagnosis and treatment

  20. Acknowledgement • Chris Cunningham & Asad Usman

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