Vaccines. Prof. Lana E. Kandalaft. Director Centre of Experimental Therapeutics, Deparment of Oncology, UNIL CHUV

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1 Vaccines Prof. Lana E. Kandalaft Director Centre of Experimental Therapeutics, Deparment of Oncology, UNIL CHUV Assisant Professor, Ludwig Cancer Reaserch Branch Adjunct Assistant Professor, University of Pennsylvania

2 Immunotherapy Cycle The Two major Players 2

3 Immunotherapy Cycle Reality 3

4 DendriticCellsat the Center of the Immunological Universe Sampling the environment Sensing pathogens Trafficking from the periphery to Lymph Nodes Presenting antigen and Shaping the immune response Inhibiting unwanted responses ( tolerance) And activating needed responses

5 Ralph Steinman Nobel Prize winner 2011 The Journal of Experimental Medicine 1973;137:

6 Whatare theydoing???

7 How are theydoingit??

8 Dendritic Cells: Shaping the immune response by the environmental signal

9 Dendritic cell activation: Toll-like receptors TLR recognize Pathogen-Associated Molecular Patterns (PAMPs) TLRs are members of the Pathogen Recognition Receptors (PRR) TLR2: bacterial lipoproteins LPS peptidoglycans TLR3: double stranded RNA TLR4: LPS Lipid A Taxol TLR5: flagellin TLR9: bacterial DNA synthetic DNA CpG INFα,β,γ TNFα IL-12 MHC II, B7 Dendritic Cell TLR7: viral small molecules Th1 Response O. Michielin

10 Dendritic Cell Maturation : The control point of cellular immunity Microbial Products/Adjuvants TLR, NOD and lectin ligands LPS, DNA,RNA Tissue Damage Uric acid, HSPs Cells of Innate Immunity pdc, NK, NK T, Neutrophils, IFN, TNF, GM-CSF Immature DC Cells of adaptive Immunity T and B cells, CD40L RANK Mature DC Steinman & Mellman

11 Immature Dendritic Cells allow peripheral tolerance Immature DC Sentinels Phagocytic Sampling normal tissue environment Traffic to LN with self antigens Instructs Immune system to be tolerant Steinman & Mellman

12 Mature Dendritic Cells allow immunity Mature DC Trigger maturation Reduce phagocytosis Present antigen Traffic to LN Interact with T cells Type I signal Steinman & Mellman

13 The Different Types of DCs

14 Immunological Goals of Vaccination Prophylactic Vaccines Priming - Generation a new Immune response Boosting of immune memory Therapeutic Vaccines Priming Reprogram pathogenic ( defective immune responses to protective ones ) Generate CD8 T cells able to kill cancer

15 Vaccination: Activation of DCs Tumor Cell MHC-I TCR Tumor Ag CD8+ CD28 B7 + + IL-2 Tumor Cell MHC-I MHC-II MHC-II Tumor Ag CpG Activated Dendritic Cell CD4+ O. Michielin

16 Dendritic Cells as Targets for vaccination Random In vivo DC Targeting Ex vivo antigen loaded DCs Peptides and adjuvants Viral vectors DNA vaccines Transduced tumor cells Specific In vivo DC Targeting Anti DC Antibody fused to a certain antigens and DC activators

17 When it all began 1890 William B. Coley Surgical Resident in New York Retrospective review in hospital records. Patient with an inoperable neck sarcoma who had developed erysipelasand experienced a spontaneous remission found out that the patient was alive 7 years Performed a clinical study -He identified a patient with sarcoma-streptococcal culture broth Erythema regression-another injection complete tumor regression free of tumor for 5 years

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19 Cancer Vaccines Different Types Chiang CL, Balint K, Coukos G, Kandalaft LE. Expert Opin Biol Ther Jan 2:1-14

20 Type of Tumor Antigens Single Antigen vaccination Multiple Antigen vaccination Personalized vaccine????????? Personalized approaches to active immunotherapy in cancer Eran Ophir, Sara Bobisse, George Coukos, Alexandre Harari, Lana E. Kandalaft Biochimica et Biophysica Acta (BBA)- August 2015

21 The prevalence of somatic mutations across human cancer types Personalized vaccines are warranted Neoantigen based vaccines are feasible in tumors with high mutational load Alexandrov et al., Nature (2013)

22 A Personalized NeoAntigen Specific Vaccine Personalized approaches to active immunotherapy in cancer Eran Ophir, Sara Bobisse, George Coukos, Alexandre Harari, Lana E. Kandalaft Biochimica et Biophysica Acta (BBA)- August 2015

23 Cheryl Chiang Kandalaft et al, JTM 2013

24 A Pilot Clinical Trial of Dendritic Cell Vaccine Loaded with Autologous Tumor for Recurrent Ovarian, Primary Peritoneal OR Fallopian Tube cancer

25 Rationale of combining antiangiogenesistherapy and metronomic chemotherapy on the tumor microenvironment TREGS x x x x x x CYCLOPHOSPHAMIDE Antiangiogenic effect VEGF ANTI-VEGF THERAPY T CELL HOMING Kandalaft et al, JTM 2013

26 Vaccine induced T cell response responding to TAAs CTE-0019 CTE-0017 CTE-0024 PBMC spots/10 5 cells 1000 CTE-0023 CTE-0016 CTE-0015 CTE-0013 CTE-0010 CTE CTE-0002 CTE CD8 T cells (P=0.13) 0.15 CD4 T cells (P=0.013) Pre Post CTE-0010 % Responder T cells % Responder T cells CTE023 CTE008 CTE025 CTE024 CTE017 PHA WT-1 NY-ESO1 Mesothelin No Antigen 0.0 Pre Post 0.00 Pre Post IFNγ producing cells/10 5 PBL Tanyi& Kandalaft, under review Alex Harari Sara Bobisse

27 Vaccine induced T cell response specific to autologous tumor antigen and achieved Tumor killing PBMC % lysis R:T cells R:T cells + MHC-I Ab NR:T cells Effector/Target Ratio * ** Tumor Volume (mm3) CTE-0001 No T cells Pre-treatment T cells Post-treatment T cells Days * ** Eran Ophir Tanyi& Kandalaft, under review

28 Vaccine induced T cell response specific correlates with clinical benefitc Tanyi&Kandalaft, under review

29 Response to vaccine is associated with improved PFS 100 Vax Non-Responders Vax Responders 100 Tumor Non-Responders Tumor Responders PFS (%) p= p= Months Months Eran Ophir Janos Tanyi Tanyi& Kandalaft et al, Submitted

30 Vaccines must be combined with other drugs Increased Immune response and survival in patients treated with cyclophosphamide 100 Cy/Bev/OCDC Percent Alive P=0.012 Bev/OCDC Fold expansion of vx-specific T cells No Cy P= Cy Months

31 Vaccine In combination with Standard of Care has Benefit Tanyi, Coukos& Kandalaft, Submitted

32 WHY?????? SUCCESSES ~ 10% clinical response rate in late stage patients Are we still studying them???>?

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34 Summary of required considerations to implement a successful vaccination strategy Martin Lluesma S, Wolfer A, Harari A, Kandalaft LE. Biomedicines May 3;4(2). pii: E10. doi: /biomedicines Review.

35 RECRUITING Lab Clinic

36 George Coukos Janos Tanyi Dan Powell Cheryl Chiang Rosemarie Mick Drew Torigian Harvey Nisenbaum Carl June Bruce Levine Our Patients Alex Harari Sara Bobisse Eran Ophir Raphael Genolet Annalisa Roberti Brian Stevenson Christian Iseli Anita Wolfer Silvia Martin Lluesma