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Tumor Immunology and Cancer Immunotherapy

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In this webinar:
Dr. Michele Ardolino, Assistant Professor at the University of Ottawa, Department of Biochemistry, Microbiology, and Immunology and Scientist Ottawa Hospital Research Institute, discusses: The body has a phenomenal weapon to fight infections and cancer: the immune system. This seminar focuses on how the immune system recognizes and shapes cancer and on how research in tumor immunology led to the development of life-saving and revolutionizing immuno-therapies.

The webinar is followed by a question & answer session.

View the video:
https://youtu.be/-a7DfHT8dU8

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Tumor Immunology and Cancer Immunotherapy

  1. 1. Michele Ardolino Scientist, OHRI Ass. Prof., University of Ottawa Canadian Cancer Survivor Network May, 2nd 2019 Tumor immunology and Cancer Immunotherapy @QFKC @ArdolinoLab @OttawaHospital @uOttawaBMI @ArdolinoLab
  2. 2. Outline Cancer and the Immune System The Immunotherapy Revolution Conclusions The Hallmarks of Cancer The Immune System Cancer Immunoediting Taking off the breaks Educating the immune response A little help from…. a foe Where are we at and where are we going?
  3. 3. In Canada, cancer is the first cause of death Cancer
  4. 4. What is cancer?
  5. 5. -Epithelial origin: CARCINOMAS (e.g. lung, prostate, breast) -Hematopoietic origin: LEUKEMIAS, LYMPHOMAS, MYELOMAS -Mesodermal origin: SARCOMAS (e.g. bones, muscles) Cancer https://www.medicalnewstoday.com/articles/323448.php
  6. 6. Cellular transformation is a multistep process Normal cells become cancer cells after a process of CELLULAR TRANSFORMATION Oncogenes: genes that make cells replicate without control Non functional tumor suppressor genes: genes that should suppress tumor growth but do not work anymore   Cancer Kotecha, et al., Oncotarget, 2016 http://beatricebiologist.tumblr.com/post/100165993576/cancer-gene
  7. 7. Several agents promote cellular transformation Cancer Hyndman, Cancer Microenvironment, 2016
  8. 8. Many cancer types Cancer is not a disease: it is a COLLECTION of diseases Cancer
  9. 9. Cancer and the immune system What makes cancer a cancer? The HALLMARKS of cancer from 2000 Hanahan D. and Weinberg R.A. Cell, 2011
  10. 10. no immunologyHanahan D. and Weinberg R.A. Cell, 2011 Cancer and the immune system What makes cancer a cancer? The HALLMARKS of cancer from 2000
  11. 11. What makes cancer a cancer? The HALLMARKS of cancer from 2000 to 2011 Hanahan D. and Weinberg R.A. Cell, 2011 Cancer and the immune system
  12. 12. Hanahan D. and Weinberg R.A. Cell, 2011 Ability of escaping the immune response is now recognized as an hallmark of cancer What makes cancer a cancer? The HALLMARKS of cancer from 2000 to 2011 Cancer and the immune system
  13. 13. What is the Immune System?
  14. 14. Cancer and the immune system https://www.stemcellimmuneregenerative.com/what-is-the-immune-system
  15. 15. Cancer and the immune system Insult Sensing Response Communication All cells in the body communicate with immune cells. Immune cells patrol the body and are continuously exposed to environmental clues. If something is wrong, the immune cells can detect it. Cancer cells acquire aberrant features that can be recognized by many immune cells that then react!
  16. 16. Cancer and the immune system Great cytotoxic capacity Kill dangerous cells Probe the target cells to detect signs of abnormalities T and NK cells
  17. 17. T and NK cells do not kill healthy cells T/NK Healthy cell spared by T and NK cells Cancer and the immune system
  18. 18. Tumor cell T and NK cells specifically kill dangerous cells T/NK Killed by T and NK cells + Healthy cell Cancer and the immune system
  19. 19. NK cell Tumor cell T cells, NK cells and other immune cells are often present in human and mouse tumors T cell B cell ???? Why don’t they kill tumor cells? Cancer and the immune system
  20. 20. Many to discover!!!! Cancer has many ways to hide from the Immune System Immunoediting
  21. 21. Outline Cancer and the Immune System The Immunotherapy Revolution Conclusions The Hallmarks of Cancer The Immune System Cancer Immunoediting Taking off the breaks Educating the immune response A little help from…. a foe Where are we at and where are we going?
  22. 22. Can we use the Immune System to fight cancer? IMMUNE SYSTEM
  23. 23. Many cancer types Cancer is not a disease: it is a COLLECTION of diseases Cancer Immunotherapy As such, there is no ONE FITS FOR ALL solution Immunotherapy can provide the ultimate personalized therapy by harnessing the patient own’s immune system against cancer
  24. 24. Cancer cell Cancer Immunotherapy “Traditional” cancer treatments (chemo and radiotherapy) activate the immune system Cancer cell Cancer cell Cancer cell Radiotherapy Chemotherapy DC CTL !!!!!! ????? Well done mate
  25. 25. Exclusion Lack of recognition Suppression How do the Cancer evade the immune response?
  26. 26. Exclusion Lack of recognition Suppression Different cancer immunotherapies target different angles of immune-evasion How do the Cancer evade the immune response?
  27. 27. Cancer Immunotherapy Cancer cell Cancer cell Cancer cell Cancer cell VACCINATION ADOPTIVE CELL TRANSFER ANTIBODIES ONCOLYTIC VIRUSES
  28. 28. Cancer Immunotherapy Cancer cell Cancer cell Cancer cell Cancer cell VACCINATION ADOPTIVE CELL TRANSFER ANTIBODIES ONCOLYTIC VIRUSES
  29. 29. Cancer Vaccines Vaccines are the “go-to” strategy for immunologists The idea is to elicit a strong immune response against tumors Problem: for pathogens, vaccines are PROPHYLACTIC not THERAPEUTIC
  30. 30. Cancer Vaccines Vaccines are the “go-to” strategy for immunologists The idea is to elicit a strong immune response against tumors Problem: for pathogens, vaccines are PROPHYLACTIC not THERAPEUTIC Prevent cancer to form in the first place e.g.: HPV vaccine prevents cervical cancer
  31. 31. Cancer Vaccines Vaccines are the “go-to” strategy for immunologists The idea is to elicit a strong immune response against tumors Problem: for pathogens, vaccines are PROPHYLACTIC not THERAPEUTIC Prevent cancer to form in the first place e.g.: HPV vaccine prevents cervical cancer Cure cancer in patients: harder to achieve because the tumor is already there!
  32. 32. Cancer Vaccines Dendritic Cell Vaccines
  33. 33. Cancer Immunotherapy Cancer cell Cancer cell Cancer cell Cancer cell VACCINATION ADOPTIVE CELL TRANSFER ANTIBODIES ONCOLYTIC VIRUSES
  34. 34. Cellular Therapy Ca Ca Ca Ca Adoptive cellular therapy is based on the idea that T cells are capable of fighting tumors Ca Ca Ca Ca T cells with different specificity Expand T cells specific for the tumor Re-infuse tumor specific T cells into the patient
  35. 35. T cell transfer works! Cellular Therapy Zacharakis N. et al, Nat Med., 2018 Before therapy 22 months after therapy Tumor
  36. 36. Cellular Therapy Ca Ca Ca Ca Adoptive cellular therapy is based on the idea that T cells are capable of fighting tumors Ca Ca Ca Ca T cells with different specificity What if there was a way to make all the T cells reactive against cancer?
  37. 37. CAR T cells: engineering T cells to fight cancer Cellular Therapy June et al. Science 2018CARs MAKE ALL T CELLS REACTIVE AGAINST TUMOR CELLS
  38. 38. Cellular Therapy Ca Ca Ca Ca Adoptive cellular therapy is based on the idea that T cells are capable of fighting tumors Ca Ca Ca Ca Instagram: whiteheadfdn http://emilywhiteheadfoundation.org/
  39. 39. Cancer Immunotherapy Cancer cell Cancer cell Cancer cell Cancer cell VACCINATION ADOPTIVE CELL TRANSFER ANTIBODIES ONCOLYTIC VIRUSES
  40. 40. Antibodies are Y-shaped molecules produced by B cells. Antibodies bind with high specificity to their antigen. Antigens are usually microbial products, but in the lab we can produce antibodies that bind to molecules present in the body for therapeutic purposes. Antibodies https://www.labce.com/spg813210_antigenantibody_interaction.aspx
  41. 41. Antibodies are Y-shaped molecules produced by B cells. Antibodies bind with high specificity to their antigen. Antigens are usually microbial products, but in the lab we can produce antibodies that bind to molecules present in the body for therapeutic purposes. Antibodies https://www.labce.com/spg813210_antigenantibody_interaction.aspx For example: we can use antibodies that activate immune cells against cancer by TAKING OFF THE IMMUNOLOGICAL BREAKS
  42. 42. Inhibitory receptors regulate immune cell activation Antibodies The activation of immune cells, including T cells, is regulated by POSITIVE and NEGATIVE signals. This balance is important to prevent auto-immunity… … but tumors often exploit the NEGATIVE signals provided by the INHIBITORY CHECKPOINT RECEPTORS to escape the immune response.
  43. 43. Antibodies Ca Ca Ca Ca Checkpoint blockade removes the break from the immune system Ca Ca Ca Ca T cells and NK cells kill tumor cells Antibodies blocking checkpoint receptors re-activate immune cells against cancer Ca Ca Ca Ca T cells and NK cells are inhibited by checkpoint receptors Ca Ca Ca Ca Ca Ca Ca Ca
  44. 44. Taking off the breaks from the immune system has a therapeutic effect! Hodi F.S. et al., New Engl. J. Med. 2010 Ipilimumab Antibodies Topalian S. L. et al., New Engl. J. Med. 2012 Tumor
  45. 45. COMBINATION COMBINATION COMBINATION Antibodies ENDLESS COMBINATION
  46. 46. Cancer Immunotherapy Cancer cell Cancer cell Cancer cell Cancer cell VACCINATION ADOPTIVE CELL TRANSFER ANTIBODIES ONCOLYTIC VIRUSES
  47. 47. Oncolytic Viruses Let’s give cancer a cold… …a made in Ottawa story Dr. John Bell OHRI/uOttawa Oncolytic Virus pioneer
  48. 48. Oncolytic Viruses Adapted from Nature Reviews Drug Discovery Antiviral responses are extremely complex and require many molecular components. Cancer cells often accumulate mutations that alter these pathways and make tumor cells more sensitive to viral infection.
  49. 49. Oncolytic Viruses Let’s give cancer a cold… HEALTHY CELLS ELIMINATE THE VIRUS CANCER CELLS CANNOT ELIMINATE THE VIRUS BY KILLING THE TUMOR, THE VIRUS ALSO STIMULATES THE IMMUNE SYSTEM
  50. 50. Oncolytic viruses in the clinic Before After Parker et al., 2008, Lancet Oncology Oncolytic Viruses
  51. 51. Outline Cancer and the Immune System The Immunotherapy Revolution Conclusions The Hallmarks of Cancer The Immune System Cancer Immunoediting Taking off the breaks Educating the immune response A little help from…. a foe Where are we at and where are we going?
  52. 52. Conclusions Immunotherapy revolutionized the clinical approach to cancer and provided hope to patients with previously incurable diseases HOWEVER There is still A LOT to do
  53. 53. Conclusions Immunotherapy revolutionized the clinical approach to cancer and provided hope to patients with previously incurable diseases HOWEVER Therapy does not work or last in many patients: what can we do to improve the response? There are many immunotherapies available: how do we choose what is the best therapy for every patient? Safety is an issue for some immunotherapies: how do we reduce toxicity without compromising efficacy?
  54. 54. Conclusions Immunotherapy revolutionized the clinical approach to cancer and provided hope to patients with previously incurable diseases HOWEVER Therapy is not efficacious or durable in many patients: what can we do to improve the response? There are many immunotherapies available: how do we choose what is the best therapy for every patient? Safety is an issue for some immunotherapies: how do we alleviate toxicity without compromising efficacy? RESEARCH IS THE ANSWER
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