describes the molecular basis behind the stage that controls the concept and application of immunotherapy in cancer management

1. Basic Principles of
Cancer Immunotherapy”
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University

2. Speaker Disclosures:
Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, AstraZeneca, Hoffman la Roche, Janssen Cilag,
Merck Serono, Novartis, Pfizer, Mundipharma, Bayer, MSD.
• The content of this presentation does not relate to any product of a
commercial interest

3. Immune System:
Thucydides (411 BC):Recovered people can
serve plague patients without catching the
disease.
Louis Pasteur: The principle of VACCINATION.
William Coley: Injection of killed bacteria into
Sarcoma lesions Tumor Shrinkage

4. Immune System:
“Immune Scenario”
Antigen
=
Peptide

5. Effective Immunogenic Response:
Pathogen Antigen
Antigen
Presenting
Cell
Identified
as Non
Self
Cytotoxic
Cell

6. Immune System: “Cellular Key-players”
Lymphocytes
T-Cells
CD8+ Identification
CD4+
Th1 Identification
Th2 Identification
Th17
Cancer
Autoimmunity
NK Cells
Low MHC Class1
+++ KIR
Treg
 immune
System
B-Cells Plasma Cells Antibodies
Myeloid Cell Macrophages
M1
Phagocytosis
& IFN-G
M2 IL4,10 & TGF-B
Pluripotent
cell in Bone
Marrow

7. Slide 4
Presented By Mary Disis at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

8. Slide 11
Presented By Mary Disis at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium

9. Tumor Antigens:
Cancer Germ-Line Genes:
Demethylation
Tumor Antigens
= Proteins
ProteasomePeptides
APCCoulie et al. NatureRevCa. 136, FEBRUARY
2014 VOLUME 14
Typical:
DC, Macrophages & B Cells
Atypical:
Mast, Eosinophil, Basophil
& ILCs.

10. Antigen Presenting Cells:
Kambayashi & Laufer. NATURE REVIEWS, IMMUNOLOGY, VOLUME 14, NOVEMBER 2014, 719

11. MHC I & II: “Human MHC”
Antigenic Machinery & Presentation:
• Definition: Set of cell surface proteins essential to recognize
foreign (non-self or diseased) molecules  histocompatibility.
http://www.differencebetween.net/science/biology-science/difference-between-mhc-and-hla/
TNF - @ & HSP

12. MHC I & II: “Human MHC”
Antigenic Machinery & Presentation:
Vigneron, Nathalie; Stroobant, Vincent; Chapiro, Jacques; Ooms, Annie; Degiovanni, Gérard; Morel, Sandra; Bruggen, Pierre van der;
Boon, Thierry; Eynde, Benoît J. Van den (2004-04-23). "An Antigenic Peptide Produced by Peptide Splicing in the Proteasome"
(http://science.sciencemag.org/content/304/5670/587). Science. 304 (5670): 587–590.

13. Adaptive Immune
Response:

14. Immune System:
“Immune Surveillance & Synapse” =
How CD8+ T-Lymphocyte Can Identify Non-Self Antigen?”
CD8+ T-Lymphocyte
TCR
CD8+ R
CD3 R
Antigen Presenting Cell
MHC 1
INF –G
IL12
Tumor
Cell
CD28 CD80/86

15. Immune System:
“Immune Surveillance & Synapse” =
How CD8+ T-Lymphocyte Can Identify Non-Self Antigen?”
CD28 CD80/86
+++ ---
GITR
OX40
ICOS
CTLA-4
PD-1/L1
TIM3
LAG3
Cytotoxic
T Cell
Non
Cytotoxic
T Cell
Check Point
Molecules

16. Keep in Mind:
• PD-1: Expressed on:
– Surface of activated CD4+ & CD8+.
– Natural Killer Cells.
– B-Cells.
– Tumor infiltrating lymphocytes.
• PD-L1 (B7-H1): Expressed on:
– Tumor Cells Surface.
• PD-L2 (B7-DC)): Expressed on:
– Dendritic cells.
– Macrophages.
– Lymphoid tissues.
• CTLA-4: Expressed on:
– T-Regulatory Cell Surface.
N.B.
• PD-L2 is not expressed on surface of tumor cells.
• PD-1/PD-L1 and 2 Interactions take place at tumor site
• CTLA-4 inhibits T-Cell activation early in lymphoid tissues
Tumor Can Inhibit
Host Immune
Response

17. How The Tumor Can Evade the
Immune Surveillance & Synapse?
Loss of MHC Function
Over Expression of
Checkpoint Inhibitors
Immunosuppressive
Microenvironment
No Antigen Presentation
or Identification
No Cytotoxic T-Cells
++ Th17 & Tregs

18. Multi-layered immunosuppression
• Tumors insulate themselves
with dense layers of
immunosuppressive stroma
• Overcoming the many layers
of interconnected and often
functionally redundant
immune suppressive
mechanisms represents a
daunting challenge for tumor-
specific T cells
• Immunotherapy can “peel
back” the layers of local
immune suppression, thereby
restoring the capacity of T
cells to eradicate the tumor

19. Immunosuppressive Tumor
Microenvironment:
Munn H.Curr Opin Immunol. 2016 April ; 39: 1–6.

20. The 3 Es of cancer immunoediting

21. The 3 Es of cancer immunoediting

22. The 3 Es of cancer immunoediting

23. The 3 Es of cancer immunoediting

24. Types of immunotherapy

25. Immunotherapeutic Strategies in
Cancer Management:
Adrian et al. Hematol Oncol Clin N Am 31 (2017) 485–498

26. Presented By Mary Disis at 2018 ASCO-SITC Clinical Immuno-Oncology Symposium
PD-L1 can be scored in tumor cells and contiguous inflammatory
mononuclear cells using Tumor Proportion Score (TPS) as
follows:
<1%: No PD-L1 expression.
>1%: Positive PD-L1 expression.
>50%: High PD-L1 Expression.
Cutoff levels in clinical trials were 1%, 5%, 10% and 50%.

27. Patterns of Response to
Immunotherapy:
• Transient worsening of findings before disease
effect becoming evident.
• Longer time to disease control than
conventional therapies.
• Durable response.
• Disease stabilization among patients who
don’t meet criteria for objective responses.

28. Immunotherapy Related Adverse
Events:

29. Cancer is a complex adaptive system
Host Immune Defenses
Phenotypically Diverse
Tumor Cell Clones
Escape the control
of normal tissue
architecture
The use of host
system to promote
progression
Genome Instability
 emergence of
clonal variants
Invasion
&
Metastases
Evasion of the
Host immune
defenses
Emergence of
drug resistant
tumor cell clones
Quoted from Dr. George Poste; The next Era in Immuno-Oncology, Presentation at Community Oncology
Alliance Annual Meeting, Orlando, FL April 15, 2016

30. Pembrolizumab and
Therapy of Metastatic Melanoma
in President J. Carter
Saturation TV Advertising

31. Cancer Immunotherapy Investment by Big Pharma:
Big Bucks, Big Projects, Big Risks?

32. Take Home Message:
• Immunotherapy is a rapidly expanding field in
cancer treatment platform.
• Immune Checkpoint inhibitors became the
treatment modality of choice for patients with
diverse types of cancers.
• Combined immunologic approaches would be
the treatment theme for many cancers.
• Prediction of response is still controversial.

33. Thank You