Vaccins anti-cancer. Claude Leclerc. 7 novembre 2011

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1 Vaccins anti-cancer Claude Leclerc 7 novembre 2011

2 2010: FDA panel passes first cancer vaccine

3 Cancer, a worldwide burden 1st cause of mortality in France In Europ, in 2006: million deaths from cancer million new cases of cancer 25 millions people throughout the world affected by cancer: Every year: - 7 millions deaths - 11 millions cases diagnosed

4 Adenocarcinomade Estimated numbers of cancer cases and deaths in the European countries (in thousands) in 2008 Ferlay J, Parkin DM, Steliarova-Foucher E. Eur J Cancer Jan 28.

5 Ethiology of cancers Infections 15-25% Hepatitis B and C viruses Helicobacter pylori Papillomavirus (HPV 16 et 18) Herpes virus type 8 (HHV8) (Kaposi) Epstein Barr virus (Burkitt Lymphoma) HTLV-1 retrovirus (leukemia) Colditz GA et al. Epidemiology - identifying the causes and preventability of cancer? Nat. Rev. Cancer. 2006

6 Oncogenic viruses and cancer Viral family Associated human cancer RNA viruses Flaviviridae HCV Hepatocellular carcinoma Retroviridae HTLV T cell leukemia HIV Carcinomas, lymphomas DNA viruses Hepadnaviridae HBV Hepatocellular carcinoma Papillomaviridae HPV16,18 Cervical carcinoma Herpesviridae EBV BL, NPC, XLP, Hodgkin L, post-transplant L KSHV (HHV8) Kaposi s S, Primary effusion L, Castelman s

7 Viral etiology of Hepatocarcinoma Oncogene (2003), TM Block, R. Jordan

8 Hepatitis B vaccine prevents liver cancer

9 HPV infection life cycle Few months to few years Up to 20 years 9 Goodman A., Wilbur D. C. Case A 37-Year-Old Woman with Atypical Squamous Cells on a Papanicolaou Smear. N Engl J Med 2003; 349:

10 Drs. Barry Marshall & Robin Warren, Univ. of Western Australia

11 Infections et Cancers Infections and Cancers Vaccination against pathogens associated to cancers induces direct prevention of related cancers: - Anti-HPV vaccination - Anti-HBV vaccination % of cancers are due to infection: But no therapeutic effect on established cancers

12 Cancer, a cell disease Radiotherapy uncontrolled proliferation Chimiotherapy Anti-angiogenic drugs Tumor Surgery

13 Is there any evidence for control of cancers by the immune system?

14 Infection and immunity Pathogens (bacteria, virus, parasite ) Virulence Stimulation of the immune system Pathology following the first exposure to the pathogen Elimination of the pathogen Protection against a second exposure to the same pathogen

15 Cancer and immunity? Cancers Transformation of normal cells Stimulation of the immune system Cancers Elimination of transformed cells Protection against cancer

16 Tumor Immunosurveillance The hypothesis was first proposed by Thomas and Burnet in Immunosurveillance: the immunological resistance of the host against the development of cancer. Immune response against tumor takes place at an early stage in tumor development - eradicating the cancer before it become apparent.

17 Kirkwood J M et al. JCO 2008;26: by American Society of Clinical Oncology

18 Early experiments (1950s) showed that mice can be immunized against tumors MCA Surgically cured mouse + Tumor cells Carcinogeninduced cancer No tumor cured mouse Tumor normal mouse

19 Tumor immunity can be tranferred to naive mice by T lymphocytes MCA Surgically cured mouse control mouse T cells T cells Tumor cells Protection No Protection

20 Observations that support immune response against cancer in patients Spontaneous regression of certain tumors Immunocompetence in cancer patients correlates with good prognosis Presence of tumor-specific immunity based on presence of CTLs, antibodies in patients Favorable prognosis of certain cancers associated with presence of immune cells at the tumor site

21 Observations that support immune response against cancer in patients Spontaneous regression of certain tumors Immunocompetence in cancer patients correlates with good prognosis Presence of tumor-specific immunity based on presence of CTLs, antibodies in patients Favorable prognosis of certain cancers associated with presence of immune cells at the tumor site

22 Association between immunodeficiency and cancer Cause of immunodeficiency primary (inherited) immunodeficiency secondary (acquired) immunodeficiency (AIDS) malaria autoimmunity lymphomas Malignancy lymphoma, cervical cancer, liver cancer, skin cancer, Kaposi s sarcoma. Burkitt s lymphoma lymphoma

23 Cancer in immunosuppressed transplant patients Table 15.1 The Biology of Cancer ( Garland Science 2007)

24 Observations that support immune response against cancer in patients Spontaneous regression of certain tumors Immunocompetence in cancer patients correlates with good prognosis Presence of tumor-specific immunity based on presence of CTLs, antibodies in patients Favorable prognosis of certain cancers associated with presence of immune cells at the tumor site

25 Type, Density, and Location of Immune Cells Within Human Colorectal Tumors Predict Clinical Outcome T cells A patient with T cells (brown) swarming near a colorectal tumor (blue) has a good shot at survival. J. Galon et al., Science 2006: Vol. 313, pp

26 The immune system can distinguish cancer cells from normal cells because cancer cells: Express very high levels of proteins/antigens found on normal cells

27 Tumor specific/associated antigens Differentiation antigens Overexpressed self antigens

28 The immune system can distinguish cancer cells from normal cells because cancer cells: Express very high levels of proteins/antigens found on normal cells Express unique proteins/antigens not found on normal cells

29 Tumor specific/associated antigens Differentiation antigens Overexpressed self antigens Mutated self antigens Non self oncoviral antigens Altered self antigens: Abnormal posttranslational/ transcriptional modification: underglycosylation

30 Effector mechanisms in cancer immunity Antibody Macrophage Cancer cell Helper T cell Natural killer cell Cytotoxic T cell

31 Antibody-mediated killing of tumor cells Y Y Y Y Y Recognition of tumor cell surface antigen by specific antibodies Tumor cell Lysis of tumor cell

32 NK cells can kill antibody-coated tumor cells by ADCC NK Cytotoxic granules Tumor cell IgG Fc Receptor IgG anti-tumor

33 Oncology Antibodies approved by the US FDA Scallon BJ, et al J Immunother 29:351 (2006)

34 Oncology Antibodies approved by the US FDA Benefit of passive immunotherapy (antibodies) in cancer patients Scallon BJ, et al J Immunother 29:351 (2006)

35 Effector mechanims in cancer immunity Antibody Macrophage Cancer cell Helper T cell Natural killer cell Cytotoxic T cell

36 Killing of tumor cells by CD8 + T lymphocytes CTL MHC I recognition Tumor cell Lysis

37 Therapeutic vaccination Therapeutic cancer vaccine Cancer Effector mechanisms Time

38 Early attempts to make cancer vaccines (1960s through 1980s) Vaccines consisted of: - Crude antigen preparations: -Irradiated or chemically treated cancer cells, cancer cell extracts - Purified tumor antigens : -Uncertainty over what is a tumor antigen. Some candidates attempted. With or without adjuvants: Alum or BCG in humans Results: Negative or marginal in mice; negative in humans

39 Tumor vaccines - Whole tumor cells: + BCG or DETOX, e.g. Melacine vaccine (cell lysates), CancerVax ( irradiated melanoma cell lines), M-Vax (hapten-treated autologous cells) and genemodified, irradiated tumor cells (GM-CSF) - Tumor antigens: MAGE-1, MAGE-3, MART-1/Melan-A, tyrosinase, gp100, MUC-1, CEA, etc. - Peptide vaccines: mutated ras, mutated p53, Her-2/neu, MART -1, gp100, MUC-1 - Heat shock proteins - DNA vaccines - Dendritic cell vaccines

40 Current human cancer vaccines show very low objective clinical response rate Response rate = 3. 8% Rosenberg, Yang & Restifo Nature Med 10:909 (2004)

41 Current human cancer vaccines show very low objective clinical response rate Benefit of passive immunotherapy Lack (antibodies) of efficacy of current in therapeutic cancer patients cancer vaccines Response rate = 3. 8% Rosenberg, Yang & Restifo Nature Med (2004)

42 Problems - Tumor derived antigens are weakly immunogenic - Tolerance or ignorance of the host (self antigens) - Immunosuppression of the host / tumor escape mechanisms Systemically Locally at the normal site of immune response (lymph nodes)

43 Problems - Tumor derived antigens are weakly immunogenic - Tolerance or ignorance of the host (self antigens) - Immunosuppression of the host / tumor escape mechanisms Systemically Locally at the normal site of immune response (lymph nodes)

44 Tumor specific/associated antigens Differentiation antigens Overexpressed self antigens Mutated self antigens Non self oncoviral antigens Altered self antigens: Abnormal posttranslational/ transcriptional modification: underglycosylation

45 Tumor Associated Antigens (TAA) Expressed on BOTH normal cells and tumor cells, but usually over-expressed on tumor cells Oncofetal antigens: alpha-fetoprotein (AFP), Carcinoembryonic antigen (CEA) Self antigens: overexpression: - c-myc in lymphomas, leukemias; HER-2/neu epidermal growth factor receptor- breast cancer (Herceptin). - MAGE-1, tyrosinase (melanoma), - Prostate specific antigen (PSA) (prostate cancer)

46 Tumor Specific Antigens (TSA) Expressed ONLY on tumor cells, induced by chemicals, radiation or viruses Altered self: - K-ras, products of normally unexpressed genes (MAGE, BAGE, GAGE), proteins of alternative reading frame, - of post-translational modification, - modification of glycosylation (mucin-ca125, MUC1). Non self antigens: viral antigens: EBNA, E6, E7, papilloma virus antigens of cervical carcinomas.

47 Targets for cancer vaccines MHC Class I MHC-associated peptides Viral Antigens Translocation peptides Mutated proto-oncogene peptides Cancer-testis antigens Autoantigens: telomerase reverse transcriptase CYPIBI WT1 Idiotypic peptides Minor histocompatibility antigens Products of genomic instability Peptides from microarray analysis Cell surface glycoproteins MHC Class II Gangliosides Mucins Differentiation antigens

48 Problems Tumor derived antigens are weakly immunogenic Need for better adjuvants or immunisation strategies

49 2006 Essai poumon GSK

50 2006 Essai poumon GSK

51 2006 Essai poumon GSK

52 Dendritic cells initiate antigen-specific immune responses most efficient of all antigen-presenting cells stimulate naïve T cells (CD4, CD8) All immunization strategies must target DCs

53 An Approach to Initiating Immunity to Cancer: Dendritic Cells Loaded with Tumor Antigens ex vivo DC precursors expanded immature DCs Tumorspecific T cells responding to dendritic cells maturing DCs presenting antigen(s) add diseaserelated antigens

54 Tumor Antigen Loading of DC X DC x tumor cell fusions Tumor lysate pulsing Tumor antigen peptide pulsing Tumor antigen gene transduction (mrna, virus) Chaperone/tumor antigen peptide pulsing

55 Summary of DC Vaccines First published trial: 1995 Since 1995, over 200 studies published, taken place in over 15 countries: NO TOXICITY However, relatively few complete or partial clinical responses reported Success Rate: Dendritic Cell vaccines 2-10%, Other Vaccines: 1-3%

56 Original Article Sipuleucel-T Immunotherapy for Castration- Resistant Prostate Cancer Philip W. Kantoff, M.D., Celestia S. Higano, M.D., Neal D. Shore, M.D., E. Roy Berger, M.D., Eric J. Small, M.D., David F. Penson, M.D., Charles H. Redfern, M.D., Anna C. Ferrari, M.D., Robert Dreicer, M.D., Robert B. Sims, M.D., Yi Xu, Ph.D., Mark W. Frohlich, M.D., Paul F. Schellhammer, M.D., for the IMPACT Study Investigators N Engl J Med Volume 363(5): July 29, 2010

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58 Kaplan Meier Estimates of Overall Survival Kantoff PW et al. N Engl J Med 2010;363:

59 Provenge approved by FDA «Studies have shown that Provenge prolongs survival by about four to 4.5 months»

60 What have we learned? Specific anti-tumor immune responses can be induced: Not only in murine models but also in patients T cell repertoire is available (CD4+ and CD8+ T cells)? Is there a role for antibodies Results have not been spectacular so far 3-5% objective responses of vaccination Clinical Responses rare, short duration BUT: Immunotherapy can be effective even against large tumor bulk

61 Which factors limit the effectiveness of tumor specific immune responses?

62 Problems - Tumor derived antigens are weakly immunogenic - Tolerance or ignorance of the host (self antigens) - Immunosuppression of the host / tumor escape mechanisms Systemically Locally at the normal site of immune response (lymph nodes)

63 How tumor cells avoid immunosurveillance 1. Altering Their Characteristics : - Loss/downregulation of MHC class I - Down-regulation, mutation, or loss of tumor antigens - Loss of costimulation 2. Suppressing the Immune Response : - Ineffective signals to CTL - Alteration in cell death receptor signaling - Immunosuppressive cytokine 3. Outpacing the Immune Response: - Tumor cells can simply proliferate so quickly that the immune response is not fast enough to keep their growth in check

64 Immunosuppressive cytokines IL-10 inhibits antigen presentation and IL-12 production. TGF-beta induces overproduction of IL-10. VEGF (vascular endothelial growth factor), avoid immune recognition, inhibit the effector function, prevent T cell activation, cytokine production.

65 Induction of Immunosuppressive cells Regulatory T cells (Treg): CD4 + CD25 + FoxP3 T cells: - Constitute 5-10% of CD4+ T cells: immunological tolerance to selfantigens, inhibition of T cell proliferation. Gr1 + CD11b + myeloid suppressor cells: - Expressing the granulocyte-monocyte markers Gr1 + CD11b +, accumulate in spleens, lymph nodes and blood of tumor-bearing mice. - Inhibiting antibody production, CTL generation, T cell function, lymphocytic proliferation, CD3 ζ chain expression.

66 Future Strategies Combination of vaccination with: Strong adjuvants Strategies to reverse escape mechanisms: CLTA4 blockade, anti-cd25 antibodies New (and better) delivery systems