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 To learn more about CCSN, visit us at survivornet.ca Follow CCSN on social media: Twitter - https://twitter.com/survivornetca Facebook - https://www.facebook.com/CanadianSurv... Instagram: https://www.instagram.com/survivornet... Pinterest - https://www.pinterest.com/survivornet...

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. 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. In Canada, cancer is the first cause of death
Cancer

4. What is cancer?

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. 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. Several agents promote cellular transformation
Cancer
Hyndman, Cancer Microenvironment, 2016

8. Many cancer types
Cancer is not a disease: it is a COLLECTION of diseases
Cancer

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. 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. 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. 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. What is the Immune System?

14. Cancer and the immune system
https://www.stemcellimmuneregenerative.com/what-is-the-immune-system

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. 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. 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. 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. 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. Many to discover!!!!
Cancer has many ways to hide from the Immune System
Immunoediting

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. Can we use the Immune System to fight cancer?
IMMUNE SYSTEM

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

26. 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

27. Exclusion
Lack of recognition
Suppression
How do the Cancer evade the immune response?

28. Exclusion
Lack of recognition
Suppression
Different cancer immunotherapies target
different angles of immune-evasion
How do the Cancer evade the immune response?

29. Cancer Immunotherapy
Cancer cell
Cancer cell
Cancer cell
Cancer cell
VACCINATION
ADOPTIVE CELL
TRANSFER
ANTIBODIES ONCOLYTIC VIRUSES

30. Cancer Immunotherapy
Cancer cell
Cancer cell
Cancer cell
Cancer cell
VACCINATION
ADOPTIVE CELL
TRANSFER
ANTIBODIES ONCOLYTIC VIRUSES

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

32. 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

33. 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!

34. Cancer Vaccines
Dendritic Cell Vaccines

35. Cancer Immunotherapy
Cancer cell
Cancer cell
Cancer cell
Cancer cell
VACCINATION
ADOPTIVE CELL
TRANSFER
ANTIBODIES ONCOLYTIC VIRUSES

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
Expand T cells
specific for the
tumor
Re-infuse
tumor specific
T cells into the
patient

37. T cell transfer works!
Cellular Therapy
Zacharakis N. et al, Nat Med., 2018
Before therapy 22 months after therapy
Tumor

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
T cells with
different
specificity
What if there
was a way to
make all the T
cells reactive
against
cancer?

39. CAR T cells: engineering T cells to fight cancer
Cellular Therapy
June et al.
Science 2018CARs MAKE ALL T CELLS REACTIVE AGAINST TUMOR CELLS

40. 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/

41. Cancer Immunotherapy
Cancer cell
Cancer cell
Cancer cell
Cancer cell
VACCINATION
ADOPTIVE CELL
TRANSFER
ANTIBODIES ONCOLYTIC VIRUSES

42. 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

43. 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

44. 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.

45. 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

46. 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

47. COMBINATION COMBINATION COMBINATION
Antibodies
ENDLESS
COMBINATION

48. Cancer Immunotherapy
Cancer cell
Cancer cell
Cancer cell
Cancer cell
VACCINATION
ADOPTIVE CELL
TRANSFER
ANTIBODIES ONCOLYTIC VIRUSES

49. Oncolytic Viruses
Let’s give cancer a cold…
…a made in Ottawa story
Dr. John Bell
OHRI/uOttawa
Oncolytic Virus pioneer

50. 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.

51. 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

52. Oncolytic viruses in the clinic
Before
After
Parker et al., 2008, Lancet Oncology
Oncolytic Viruses

53. 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?

54. 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

55. 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?

56. 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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Many thanks:
lab
Honorary member
Karen Jardine
Marie-Claude Bourgeois-Daigneault
Surgical Equipe
Carolyn Nessim
James Villeneuve
Stephanie Johnson-Obaseki
Rebecca Auer
Joan Sealy Trust
Lab members
Cynthia Chan
Denis Qeska
Jonathan Hodgins
Lysanne Desharnais
Maria Park
Serena Cortés-Kaplan
Shaad Hasim