Basic principles of cancer immunotherapy

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

1. Basic Principles of Cancer Immunotherapy ” M ohamed A bdulla 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” Intruder APC Identification Immune Response Disease Effect Host Effect Antigen = Peptide Intruder Innate Immunity Adaptive Immunity

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

6. Immune System: “Cellular Key-players” 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 Proteasome Peptides APC Coulie 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 IMMUNOGENICITY

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 Cancer is a Hypermutable Disease

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