This document provides an overview of principles of cancer immunotherapy. It discusses anti-cancer immunity mechanisms like antigen presentation and T cell activation. It also examines how cancers can evade the immune system through strategies like low MHC expression and immunosuppressive factors. The document then reviews clinical applications of immunotherapy including cytokines, monoclonal antibodies, adoptive cell transfer, vaccines, and checkpoint inhibitors. Combination therapies are showing promise for enhancing anti-tumor responses.

1. Principles of
Cancer Immunotherapy
2017
Ihor Arkhypov1,2
1Bogomolets National medical
university,
2Ukrainian medical student’s
association
1

2. Courses and Internships:
2014 VIII School-seminar “Biophysical methods of research”, Kiev, Ukraine;
2016 Internship in General Surgery department, Semmelweis University,
Budapest, Hungary – by IFMSA Exchange program (2016);
2016 III School-seminar on stomach surgery, Kiev, Ukraine;
2016 Participation in Cancer Immunotherapy School, Kiev, Ukraine;
2017 Internship in the Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg and
Department of Dermatology, Venereology and Allergology, University Medical Center
Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany (2017).
2017 Internship in Nacional Cancer Institute, Kiev, Ukraine on Medical and Surgical Oncology
CV
2
Memberships:
2015-present Member of Ukrainian Medical Student’s Association;
2015-present Council member of O.A. Kysil Students’ Scientific Society;
2016-present Member of non-profit organization INgenius.
Publications:
•7 abstracts of reports on the conferencies;
•Litvinova N. Yu., Arkhypov I.G., Dubenko D. Ye.Angiogenesis: normal and pathological.J. Heart & Vessels
(2015) 4 (52): 95-99 (in Ukrainian).

3. Intro
Part 1. AntiCancer immunity
Part 2. Cancer surviving
Part 3. Clinical impementation
Conclusions
Content
QUIZ
Discussion
3

4. • To improve knowledge about anti-cancer
immunity and escape mechanisms of cancer
• To discuss modern methods of immunotherapy
• To develop critical view on research in this field
• To practice English:)
• Stimulate to read more :)
Goals of workshop
4

5. Evolution of cancer cell
Hanahan, Douglas, and Robert A. Weinberg. "Hallmarks of cancer: the next generation."
cell 144.5 (2011): 646-674. 5

6. Part 1
AntiCancer
immunity 6

7. Can tumors be recognized?
7

8. 1. Embrionic
2. Abnormal posttranslational modification
3. Factors of differentiation
4. Mutated oncogene or tumor suppressor gene
5. Oncoviral protein
Tumor antigens
Coulie, Pierre G., et al. "Tumour antigens recognized by T lymphocytes: at the core of cancer
immunotherapy."Nature Reviews Cancer 14.2 (2014): 135-146. 8

9. AntiCancer adoptive cellular immunity
1. Release of cancer cell antigens
2. Cancer antigen presentation
3. Priming and activation
4. Trafficing of T cells to tumors
5. Infiltration of cancer cells by T cells
6. Recognition
7. Killing
9

10. T cell activation
10

11. 11
T cell receptor

12. Costimulatory molecules
12

13. Natural killer cells (innate immunity)
Receptors on NK cells:
1) Inhibitory
• killer Ig-like receptors (KIRs)
• CD94/NKG2A
2) Activatory
• “natural cytotoxisity receptors”
(NCR): NKp46, NKp30, NKp44;
• CD16, responsible for antibody-
dependent cytotoxicity;
• NKG2D and DNAM-1, that recognize
de novo expressed ligands on
transformed cells
Koch et al.,2013; Fionda et al.,2015; Rajalingam, 2016; McWilliams et al., 201613

14. Natural killer cells
14

15. Interleukins
15

16. 1 VS 2 type
16

17. Interleukins & crosstalk's
17
DC - IL1β, IL12, IL18 – NK – INFγ, TNFα, GM-CSF
DC - IL12 – Th 1 – INFγ – CD8+ T cells

18. • Natural killer cells
• Cytotoxic T cells CD8+
• Helper T cells CD4+ (Type 1)
• M1 macrophages
• Dendritic cells
• B cells ?
AntiCancer immunity
18

19. 19
Why antibodies are not so effective for
killing cancer cells as for killing bacteria's
?

20. When you avoided an immune response!
20

21. Part 2
Cancer
surviving 21

22. •Low MHC
•No co-stimulatory
molecules
Strategies
22

23. Strategies
23
1. Low/- MHC, low/- costimulatory molecules
2. Antigenic heterogeneity
3. Immunosuppressive factors
4. Protumorogenic environment

24. 24
Immunosuppressive factors, checkpoints

25. 25
Protumorogenic environment

26. 26
T regulatory cells

27. • Cancer cells
• CCL2, CXCL5
• MDSCs
27
Myeloid-derived suppressor cells

28. 28

29. 29
Chronic VS acute inflammation

30. +Angiogenesis
+Growth factors
30
Chronic VS acute inflammation
IL-6, TNFα,
IL-1β,
CCL2,
CCL5Short exposure
(hours, days)
Long-term exposure
(weeks, mounths)
Immune
stimulation
Immune
suppression

31. A. Surface
molecules
B. Cargo
31
Exosomes

32. 32
Tumor-derived exosomes

33. • Chronic inflammation
• Low/- MHC, low/- costimulatory molecules
• Macrophages type 2 = tumor associated macrophages (TAMs)
• Tregs
• MDSCs
• Regulatory DCs
• Regulatory B cells
• Exosomes
Cancer surviving
33

34. Perforines &
Granzymes
34
QUIZ
TCR
Cytotoxic T cells
Th1
Th2
M1
M2
DC
MDSC
T regs
iNOS
Arginase-1
IL-2
IL-10
PD-1
PDL-1
CTLA-4
Cancer cell
Antigen
presentation

35. 35
Part 3
Clinical
trials & usage

36. • Cancer immunotherapy – is a therapy aimed
to enhance the power of host immune system
for the treatment of malignancies
• Goals:
– ↑ Antitumor response
– ↓ Immunosuppresssion
– ↑ Immunogenicity of tumors
36
Definition

37. Kirkwood et al., CA Cancer J Clin., 201337
History

38. • Heat-inactivated bacteria to
induce inflammation (acute)
38
Coley toxin

39. 1. Cytokines and growth factors
2. Monoclonal antibodies
3. Adoptive immunotherapy
4. Tumor cell vaccination
5. Immune gene therapy
6. Neutralization of immunosuppression
39
Types of immunotherapy
V. Umansky Cancer immunotherapy school, Kyiv, 2017

40. • TNFα, INFγ
• IL-2, IL-4, IL-12, IL-15, IL-18
• Combination approaches
– Cytokines + radiotherapy
– Cytokines + chemotherapy
• 2-3 cytokines
40
1. Cytokines and growth factors

41. • capillary-leak syndrome + decreased systemic vascular
resistance (fever, hypotension,cardiac arrhythmia, lethargy,
renal insufficiency, hepatic dysfunction, body edema,
pulmonary edema, and confusion;
• other side effects can also include nausea, diarrhea, rash,
anemia, thrombocytopenia,lymphocytosis, and neutrophil
chemotactic defect
• predisposition patients to infections
41
Side effects
1. Cytokines and growth factors

42. 42
IL-2 for melanoma
Between 1985 and 1993, 270 patients with
metastatic melanoma enrolled into eight clinical
trials in multiple centers using highdose IL-2
• overall response rates of 16% (43 patients),
• 10% partial and 6% complete;.
• the longest response duration of >12 years ongoing
• FDA approved IL-2 for the treatment of metastatic
melanoma in 1998.
Atkins et al., 1999
1. Cytokines and growth factors

43. 43
2. Monoclonal antibodies

44. 44
3. Adoptive immunotherapy

45. 45
3. Adoptive immunotherapy

46. 46
Dendritic cell vaccine
3. Adoptive immunotherapy

47. 47
Adoptive transfer of Tumor Infiltrating Lymphocytes
3. Adoptive immunotherapy

48. 48
Adoptive transfer of Tumor Infiltrating Lymphocytes
3. Adoptive immunotherapy
DeVita Hellman and Rosenbergs Cancer
Principles and Practice of Oncology 10E (2015)

49. • chronic
lymphocytic
leukemia (CLL)
after treatment
with chemotherapy
followed by an
infusion of
autologous anti-
CD19 CAR T cells
49
autologous anti-CD19 CAR T cells
Kochenderfer JN, Rosenberg SA. Treating B-Cell cancer with T cells expressing anti-
CD19 chimeric antigen receptors. Nature Rev Clin Oncology 2013;10:267-276
3. Adoptive immunotherapyc

50. 50
Combinations
Rosenberg SA, Yang JC, Sherry RM, et al. Durable complete responses in heavily pretreated patients with
metastatic melanoma using T-cell transfer immunotherapy. Clin Cancer Res 2011;17:4550–4557.
3. Adoptive immunotherapy

51. 51
6.Neutralization of immunosuppression
•Blocking inhibitory checkpoints (PD-1, CTLA-4)
•Blocking regulatory cells
Tregs deplition (antiCD25 mAB)
MDSC inhibition
•Blocking homing of regulatory cells (anti CCR4 mAb)

52. 52
Checkpoint inhibitors
6. Neutralization of immunosuppression
antiPD-1 mAb – nivolumab
antiCTLA-4 mAb - ipilimumab

53. 53
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated
Melanoma
6. Neutralization of immunosuppression
J. Larkin et al., 2015

54. 54
6. Neutralization of immunosuppression
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated
Melanoma
J. Larkin et al., 2015

55. 55
6. Neutralization of immunosuppression
Combined Nivolumab and Ipilimumab or Monotherapy in Untreated
Melanoma
J. Larkin et al., 2015

56. • Modulates p38 MAPK signaling in MDSCs
• ↓MDSCs, ↓NO production
• ↑proliferation of CD8+ T cells
56
Low dose Paclitaxel VS MDSCs
Sevko, Alexandra, et al. "Antitumor effect of paclitaxel is mediated by inhibition of myeloid-
derived suppressor cells and chronic inflammation in the spontaneous melanoma model." The
Journal of Immunology 190.5 (2013): 2464-2471.

57. 57
Discussion
1. What is the biggest
trouble to overcome in
cancer immunotherapy?
2. Which type of cancer
immunotherapy is better?

58. • Cancer immunotherapy is undergoing its “Golden
era”
• Physicians who deal with cancer should be
familiar with immunotherapy methods and
remember about side effects
• There is a need for comparative trials between
target therapy & immunotherapy and about
simultaneous implementation
58
Conclusions

59. 59
Thank you for
attention!