The document discusses immuno-oncology and the relationship between cancer and the immune system. It provides an overview of topics that will be covered in an upcoming webinar, including advances in immuno-oncology for different cancer types and combination immunotherapy approaches. The document then reviews key topics in more depth, including how immuno-oncology focuses on improving the body's immune response against cancer and recent immunotherapy approvals. It also discusses how cancer can evade the immune system and strategies for cancer immunotherapy, such as manipulating co-stimulatory signals, enhancing antigen presenting cells, and using cytokines, monoclonal antibodies, and cancer vaccines.

1. Cancer and the
Immune System
Dr. B. K. Iyer

2. Webinar topics ahead
1. Review of immuno-oncology
2. Advances in immuno-oncology
3. Immuno-oncology: understanding function & dysfunction of the immune
system in cancer
4. Melanoma as a model tumour for immuno-oncology
5. Recent immunotherapy advances changing standard of care in
metastatic melanoma
6. Evolving role of immunotherapy in prostate cancer
7. What future opportunities may immuno-oncology provide for improving
the treatment of patients with lung cancer?
8. Emerging immunotherapies for renal cell carcinoma
9. Combination immunotherapy approaches
10. Evolution of end points for cancer immunotherapy trials
11. Can immuno-oncology offer a truly pan-tumour approach to therapy?

3. A look-ahead
• Immuno-oncology
• Tumors and Metastasis
• Oncogenes and Cancer Induction
• Tumor Antigens
• Tumors and the Immune Response
• Immunotherapy

4. Immuno-oncology
• Immuno-oncology is a new area of medicine
that focuses on the development and
delivery of therapies that improve the body's
intrinsic potential for generating an effective
immune response against cancer.
• Although immuno-oncology is still in its
infancy, immunotherapy has been yielding
clinical results for some time, and the most
recent agents entering the clinic look even
more promising.

5. Immuno-oncology
• In April 2010, sipuleucel-T became the first
therapeutic vaccine to be approved by US
FDA for the therapy of prostate cancer.
– Subsequently, in 2011, ipilimumab, a fully human
monoclonal antibody which blocks cytotoxic T-
lymphocyte-associated antigen-4, became the first
agent approved in the EU for the treatment of
adult patients with unresectable or metastatic
melanoma who have received prior therapy that
showed an overall survival benefit in a randomised
phase III trial.

6. Immuno-oncology
• Hence, many think that immunotherapy
should be considered alongside
1. Surgery,
2. Chemotherapy and
3. Radiotherapy
4. As the 4th
cornerstone of anticancer treatment.
• Influencing the body’s immune system to give
an immune response against cancer is
immuno-oncology's primary focus.

7. Cancer and the
Immune System

8. Cancer
“altered self-cells that have escaped normal
growth regulation mechanisms”
neoplasm: tumor
benign vs. malignant
metastasis: spreading of cancerous cells via
blood or lymph to various tissues

9. Metastasis
22.1

10. Types of Cancers
carcinoma: endodermal/ectodermal tissue
leukemia/lymphoma: hematopoeitic stem cells
sarcoma: mesodermal connective tissues

11. What makes cancer
“cancer”?
1. decreased requirements for growth
factors and serum
2. are no longer anchorage dependent
3. grow independently of density
normal cells:
eventually enter Go
confluent monolayer CHECKPOINT FAILURE
contact inhibition

12. Malignant Transformation
• are like in vitro cancers
• two phases
1.initiation (changes in genome)
2.promotion (proliferation)

13. Malignant Transformation
• chemical and physical carcinogens
• virally induced transformation
• cultured tumors: good models for study
• cancer cells are basically immortal

14. Oncogenes…
oncogene: “cancer
gene”; often found in
viral genomes
proto-oncogene:
cellular counterpart
which can be turned
into an oncogene

15. What can go right?
• induction of cellular
proliferation
• inhibition of cellular
proliferation, a.k.a. tumor-
suppressor genes
• regulation of programmed
cell death

16. What can go wrong?
• chromosomal translocations
• tandem repeats: HSRs
• mutations in proto-oncogenes
• viral integration
• growth factors and their receptors

17. Induction of Cancer
Fig. 22.2

18. Induction of Cancer

19. To Visualize!
• http://science.education.nih.gov/suppleme
nts/nih1/cancer/activities/activity2_animati
ons.htm

20. Tumors of the Immune System
• Lymphomas
– Solid tumors w/in lymphoid tissue (bone marrow,
lymph nodes, thymus)
– Hodgkin’s & non-Hodgkin’s
• http://www.lymphomainfo.net/
• Leukemias
– Proliferate as single cells
– Acute or Chronic depending on the progression of
disease
• Acute- appear suddenly and progress rapidly;
arise is less mature cells (ie ALL, AML)
• Chronic- much less aggressive and develop
slowly; mature cells (ie CLL and CML)

21. Tumor Antigens
• TSTAs
– Tumor Specific Transplantation Antigen
• TATAs
– Tumor Associated Transplantation Antigen

22. TSTAs
• Unique to tumor cells
• DO NOT occur on normal cells in the body
• Novel proteins created my mutation presented
on class I MHC
• Can either be chemically/physically induced or
virally induced tumor antigens

23. Chemically/Physically Induced
• Specific Immunologic Response that can
• Protect against later challenge by live cells
• Of the same line but not other tumor-line Cells.
• Methylcholanthrene / UV light

24. Virally Induced
• Express tumor antigens shared by all tumors induced
by the same virus
• Burkitt’s Lymphoma
– Epstein Barr
• HPV

25. TATAs
• NOT unique to tumor cells
• DO occur on normal cells in the body
• So where’s the problem?
– Fetal/adult presence
– Concentration of Growth Factors and Growth
Factor Receptors

26. TATAs cont’d
• Oncofetal Tumor Antigens (AFP & CEA)
– Normally appear in fetus before
immunocompetence
– Later recognized as non-self
• Oncogene Proteins
• Human Melanomas

27. Virally Induced Tumors
• Virally induced tumors have the same
antigens for each tumor caused by that
virus.
• HPV

28. Immune Response to Tumors
• Mostly a cell-mediated
response
• NK Cells
– Not MHC restricted
– Fc receptor binds to antibody
coated tumor cell  ADCC
– Chedieak-Higashi syndrome
• Macrophages
– Not MHC restricted
– Elicits ADCC
– TNF-alpha
• Immune Surveillance Theory

29. So, you have a tumor cell. Now
what?
• You need three things:
1. “See” the cancer
• Ternary complex and costimulation by B7
1. Activate lymphocytes
• Release IL-2, IFN-gamma, and TNF-alpha
1. Cancer cells must be susceptible to killing
• CTL lysis, macrophages, NK cells
Info From:
http://www.brown.edu/Courses/Bio_160/Projects1999/cancer/imevstca.html#Introduction

30. But if the body has all
these defenses, why do so
many people still have
cancer?

31. Conniving Cancer
• Bad antibodies?
– Some antibodies do not protect against tumor growth,
but also ENHANCE it.
– Release of immunosuppressive cytokines
• transforming growth factor-beta (TGF-beta), interleukin-10
(IL-10) and vascular endothelial growth factor (VEGF)
• Hide and go Seeking Antigen
– Antigens actually seem to “hide” in the presence of
antibody
– Also, some cancer cells completely shed themselves
of the antigen

32. Effect TGF-beta IL-10 VEGF
Inhibition of T-cell growth
+ - +
Inhibition of CTL differentiation
+ + +
Inhibition of cytokine production
+ + -
Induction of T-cell anergy
+ - -
Downregulation of cytotoxic potential
+ + -
Inhibition of antigen presentation
+ + -
Shift in the Th1-Th2 balance towards
Th2
+ + -
Downregulation of
adhesion/costimulatory molecules
+ + -
Resistance to CTL-mediated lysis
- + -
Source: Chouaib et al 1997

33. Conniving Cancer cont.
• Reduction in
Class I MHC
Molecules

34. And the final blow…
• Lack of Co-
Stimulatory
Signal

37. Cancer Immunotherapy
• Manipulation of Co-Stimulatory Signal
• Enhancement of APC Activity
• Cytokine Therapy
• Monoclonal Antibodies
• Cancer Vaccines

38. Manipulation of Co-Stimulatory
Signal
• Tumor immunity can be enhanced by providing the
co-stimulatory signal necessary for activation of CTL
precursors (CTL-Ps)
• Fig. 22.11a

39. Manipulation of Co-Stimulatory
Signal Cont.
• Basis for Vaccine
– Prevent metastasis after surgical removal or
primary melanoma in human patients

40. Enhancement of APC Activity
• GM-CSF (Granulocyte-macrophage colony-
stimulating factor)
remember: CSFs are cytokines that induce the
formation of distinct hematopoietic cell lines
• Fig 22.11b

41. Cytokine Therapy
• Use of recombinant cytokines (singly or in
combination) to augment an immune
response against cancer
– Via isolation and cloning of various cytokine
genes such as:
– IFN-α, β, and γ
– Interleukin 1, 2, 4, 5, and 12
– GM-CSF and Tumor necrosis factor (TNF)

42. Cytokine Therapy Cont.
I. Interferons
• Most clinical trials involve IFN-α
• Has been shown to induce tumor regression in
hematologic malignancies i.e. leukemias,
lymphomas, melanomas and breast cancer
• All types of IFN increase MHC I expression
• IFN-γ also has also been shown to increase
MHC
II expressionon macrophages and increase
activity of Tc cells, macrophages, and NKs

43. Cytokine Therapy Cont.
II. Tumor Necrosis Factors
• Kills some tumor cells
• Reduces proliferation of tumor cells without
affecting normal cells
How?
• Hemorrhagic necrosis and regression, inhibits
tumor induced vascularization (angio-genesis)
by damaging vascular endothelium

44. Cytokine Therapy Cont.
III. In Vitro-Activited LAK & TIL cells
A. Lymphocytes are activated against
tumor
antigens in vitro
• Cultured with x-irradiated tumor cells
in
presence of IL-2
• Generated lymphokine activated
killer
cells (LAKs), which kill tumor cells
without affecting normal cells

45. In Vitro-Activated LAK and TIF cells Cont.
B. Tumors contain lymphocytes that have
infiltrated tumor and act in anti-tumor
response
• via biopsy, obtained cells and
expanded population in vitro with
• generated tumor-infiltrating lympho-
cytes (TILs)

46. Monoclonal Antibodies
• Anti-idiotype
• Growth Factors
-HER2
• Immunotoxins

48. Cancer Vaccines
• Genetic
• Biochemical

49. HPV
Human Papilloma Virus
• E6
• E7

50. From Normal to Abnormal:

51. For more info
• HPV
• Cancer Vaccines

52. C
C is for
Cancer!