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The fight against Cancer: can our immune system deliver a knockout blow?

The fight against Cancer: can our immune system deliver a knockout blow?. R ole of our immune system in Cancer prevention and development A potential roll of an ‘autoimmune antigen’ in the treatment of Chronic Myeloid Leukaemia. Dr. David Pryce

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The fight against Cancer: can our immune system deliver a knockout blow?

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  1. The fight against Cancer: can our immune system deliver a knockout blow? Role of our immune system in Cancer prevention and development A potential roll of an ‘autoimmune antigen’ in the treatment of Chronic Myeloid Leukaemia Dr. David Pryce Bangor UniversitySchool of Medical Sciences d.w.pryce@bangor.ac.uk https://www.linkedin.com/in/david-pryce-22702719/ https://www.bangor.ac.uk/sms/staff/pryce.php

  2. Our Immune System Innate immunity Adaptive immunity No Memory Memory Protects the body from pathogens • Five major groups of potential pathogens: • Virus, bacteria, fungi, protozoa and helminths (worms). • 208 viruses • 538 bacteria • 317 fungi • 57 parasitic protozoa • 287 worms • (CDC figures 2011) ‘The boy in the bubble’ David Phillip Vetter 1971 –1984 Severe Combined Immuno-Deficiency (SCID) Cause of death: Burkitt’s Lymphoma

  3. Our Immune System How does the immune system recognise the bad guys? Immune Cells and antibodies ‘survey’ our tissues and body

  4. Our Immune System How does the immune system recognise the bad guys? Histocompatibility complexes

  5. Our Immune System Adaptive immunity The set of adaptive immune cells each person produces is unique to them • Every immune cell set activates, develops and adapts to the ‘experiences’ our lives • The environment we live in • Who we choose as our ‘partner’ • Who we ‘cohabitate’ with • ’Positive outlook’ on life • The Aging process

  6. Our Immune System Innate immunity Adaptive immunity Autoimmune Disease • Autoimmune disease can result if our immune inappropriately ‘attacks’ the body’s own cells • More than 80 Autoimmune diseases have been classified • Most are chronic and incurable • Most Autoimmune diseases effect Women more than men Loss of regulation

  7. Our Immune System and Cancerwhere’s the link?

  8. Cancer Research The earliest recorded theory of Human cancer was based on the humoral theory of disease Hippocrates (460–370 BCE). He was postulated that the disease was due to an excess of “black bile” • ‘Modern’ cancer research really began in the 19th century • Exposure to aromatic amines and bladder cancer • Snuff with nasal polyps • Soot with scrotal cancer • Reproductive factors with breast cancer • Set the stage for the identification of carcinogens chemical agents that can cause cancer • Rudolf Virchow: cancer is a disease of cells. This hypothesis lasted about 1,900 years!

  9. Cancer Research Our understanding in the 21st century Rudolf Virchow was correct cancer is a disease of cells. More precisely Cancer arises due toMutation(s) in…. Our Genetic code and/or Our Epigenetic code Mutation(s) can be Inherited and/or developed GeneticMutation(s) Epigenetic Mutation(s)

  10. Human Cancers About 93% of our cells are ‘blood cells’: Red Blood Cells, platelets or bone marrow cells At least 50 other types of nucleated cells make up the rest (Bianconi et al., 2013)

  11. Our Immune System and cancer – the link! Innate immunity Adaptive immunity ‘Natural killers’ No Memory B cells, T cells Memory Can our immune system ‘control’ Cancer? Mutation(s) Adapted from: http://www.emedmd.com/content/cancer-immunity-and-clinical-oncology-cancer-immunosurveillance

  12. Cancer Treatments Hanahan, D. and Weinberg, R. A. (2011) ‘Hallmarks of cancer: the next generation.’, Cell, 144(5), pp. 646–674. doi: 10.1016/j.cell.2011.02.013.

  13. Cancer Immunotherapy • Immunotherapy…. • ‘Specific’ attack • Can stimulate Immune system • Can Help Target drugs • ‘Conventional’ therapy…. • Often Relatively non-specific • Radiation treatment • Chemotherapies

  14. Monoclonal Antibodies Well over 200 monoclonal antibodies have passed through some kind of clinical trial AMA (generic) Naming convention Monoclonal antibody list Monoclonal antibodies: versatile platforms for cancer immunotherapy Louis M. Weiner, Rishi Surana, Shangzi Wang Nature Reviews Immunology 10, 317-327 (May 2010) doi:10.1038/nri2744 Review http://www.vetmed.wsu.edu/tkp/search.aspx

  15. Research Introduce some of the latest work from my research group A potential roll of an ‘autoimmune antigen’ in the treatment of Chronic Myeloid Leukaemia

  16. ‘Blood cancers’ Leukaemic Stem Cell? Lymphocytic leukaemia Acute lymphoblastic leukemia (ALL) Chronic lymphocytic leukemia (CLL) Myelogenous leukaemia Acute myelogenous leukemia (AML) Chronic myelogenous leukemia (CML) CML Mulitple myeloma plasma cells in bone marrow form solid tumors. http://www.nature.com/nature/outlook/leukaemia/

  17. Chronic Myeloid Leukaemia • Chronic Myeloid Leukemia (CML) • Develops from a mutated hematopoietic stem-cell/common myeloid progenitor • That contains a BCR-ABL ‘fusion gene’ • 8% of all leukaemias and 0.2% of all new cancer cases (UK 2013) • Incidence and prevalence gradually rising developed countries highest rates.

  18. Chronic Myeloid Leukaemia • ‘3–stage’ diseaseInitial chronic phase –to- blast crisis • Mean age of diagnosis: UK - 64.4 males, 66.5 females • Very successful drug therapy • Tyrosine kinase inhibitors (TKI) • Reduced the annual mortality rate10-fold • Can extend survivability to close to the normal expected lifespan.  Do we need more drugs? Weisberg, E., Manley, P. W., Cowan-Jacob, S. W., Hochhaus, A., & Griffin, J. D. (2007). Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nature Reviews Cancer, 7(5), 345–356.

  19. Chronic Myeloid Leukaemia • TKI treatment usual ‘life–long’. • Compliance to treatment regimes essential • Treatment withdrawal requires minimum 2-year of therapy • ≅20% patients serious side effects/quality of life issues • Resistance: BCR-ABL mutations, and ‘other’ pathways • annual cost of first-line TKI (Imatinib) therapy £19,000 - £38,000 • 2ndand 3rd generation TKIs at least10-20% more expensive • "Further good-quality studies are needed” Weisberg, E., Manley, P. W., Cowan-Jacob, S. W., Hochhaus, A., & Griffin, J. D. (2007). Second generation inhibitors of BCR-ABL for the treatment of imatinib-resistant chronic myeloid leukaemia. Nature Reviews Cancer, 7(5), 345–356.

  20. Chronic Myeloid Leukaemia • Treatment summary • TKI therapies are remarkable success story, but not • perfect drugs • N.I.C.E recommendations • "Further good-quality studies are needed to investigate • the efficacy of Imatinib in combination with other • Treatment options” • N.I.C.E. are not alone! • There is a growing consensus that new treatments for • CML are urgently required 1,2 1 Holyoake, T. L. & Helgason, G. V. Do we need more drugs for chronic myeloid leukemia? Immunological Reviews 263, 106–123 (2015). 2 Leukemia, E. I. C. M. et al. The price of drugs for chronic myeloid leukemia (CML) is a reflection of the unsustainable prices of cancer drugs: from the perspective of a large group of CML experts. Blood 121, 4439–4442 (2013).

  21. Our Immune System Innate immunity Adaptive immunity Autoimmunityin Cancer therapy • Reactivating an ‘exhausted immune may reinvigorate the immune ‘attack’ on specific targets • Amazing successful results using monoclonal antibodies therapies that target key ‘immune checkpoints’ Remove the brakes!

  22. YRNAs 4 know genes, numerous psuedogenes N-term ‘surface’ Y-RNA The TROVE2 protein • Conserved region - required for DNA replication • Up-regulated in tumours • ‘small- YRNAs’ biomarkers Central cavity ssRNA • Roles with Ro60 • RNA quality control • Molecular associationswith other protein Ro60 Surfaces that Interact with RNAMolecular surface representation of Ro structure (Xenopuslaevis)* Y-RNA interaction regions are colouredgreen single-stranded RNA interaction regions are colouredteal.*(78% identical to human Ro60) Adapted from Stein et al (2005). Structural insights into RNA quality control: The Ro autoantigen binds misfolded RNAs via its central cavity. Cell 121, 529–539.

  23. Yellow correspond to human Ro60 amino acids. Sjögren’sMajor epitope • Ro60 ‘autoantigen’ • Components: • TROVE2 (Ro60, SSA2) • TRIM21 (Ro52, SSA1) • YRNAs • Autoantibodies against TROVE2 • Detected in – • Sjögren’s syndrome (38–90%)* • Systemic Lupus Erythematosus (24–60%)* • Subacutecutaneous lupus erythematosus (70–100%)* • The ‘first’ autoantibodies detected in these diseases - up to 4 years prior to patent disease • Detected in number of other ‘systemic’ autoimmune disease • *Depends on study and techniques used for detection TROVE2 Autoimmune Epitopes and Disease Lupus Major Epitope 1 - Major Epitope2 - Epitopes recognized by anti-Ro60 autoantibodies overlap with RNA binding regions Note –additional surfaces that contact the bound Y-RNA, or that contact misfolded RNAs, may not yet have been identified. Adapted from Wolinand Reinisch(2006). The Ro 60 kDa autoantigen comes into focus: Interpreting epitope mapping experiments on the basis of structure. Autoimmunity Reviews 5, 367–372.

  24. Main Objectives siRNA(s) with most effective TROVE2 knockdown Optimize their transfection per cell line Validate specificity of anti TROVE2 primary antibodies Determine ‘viability’ of knockdown phenotype TROVE2 Anti-Sense RNA depletion siRNAs Anti-sense oligonucleotides (ASO) microRNAs (miRNA)

  25. TROVE2 Anti-Sense RNA (CML cell lines) ‘knocking down’ TROVE2 in CML Blast Crisis cell lines results in increased susceptibility to TKI drugs

  26. The fight against Cancer: can our immune system deliver a knockout blow? Thank you for listening

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