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Immunity and Tumors Cancer Immunotherapy. Immunity and Tumors 1890s Coley treats patients with bacterial extracts 1950-1960s Burnet and Thomas- Immune-surveillance.

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Presentation on theme: "Immunity and Tumors Cancer Immunotherapy. Immunity and Tumors 1890s Coley treats patients with bacterial extracts 1950-1960s Burnet and Thomas- Immune-surveillance."— Presentation transcript:

1 Immunity and Tumors Cancer Immunotherapy

2 Immunity and Tumors 1890s Coley treats patients with bacterial extracts 1950-1960s Burnet and Thomas- Immune-surveillance Hypothesis Major function of the immune system is to recognize and destroy arising malignantly transformed cells 1957 Prehn and Main- The origin of modern tumor immunology

3 NormalNormal InitiationInitiation PromotionPromotion P r o g r e s si o n proliferationdifferentiation apoptosis proliferation Pathogenesis of neoplasia DNA damage (chemical, phisical, biologic) DNA damage Clonal evolution Additional mutations

4 I tumori e la risposta immunitaria I tumori derivano da tessuti normali I tessuti normali non inducono risposta immunitaria Esiste una risposta immunitaria contro i tumori?

5 Limmunosorveglianza 1959 Thomas e Burnet: limmunosorveglianza The immune system maintains vigil over both alien microorganisms and altered somatic cells Il tumore è antigenico ed immunogenico 1)Evidenze sperimentali: Il trapianto di tumori in ospiti singenici viene rigettato, mentre il trapianto di tessuti normali viene accettato Il rigetto di tumori spontanei o indotti conferisce protezione 2) Evidenze cliniche: Linsorgenza di tumori è piu alta in assenza di competenza immunologica (immunodeficienze congenite o acquisite)

6 Evidenze di immunogeneticità dei tumori Sarcoma Resezione chirurgica Nessuna crescitaCrescita del tumoreNessuna crescita Topo naive Vaccinazione con cellule tumorali Topo vaccinato

7 - The immune system of inbred mice can recognize antigens expressed by tumor cells induced by chemical carcinogens - Such recognition results in rejection of a subsequent challenge of the same but not a different tumor in previously immunized animals - Specificity and memory - The immune cells but not antibodies can mediate this reaction Conclusions from experiments on transplanted tumors

8 Evidenze sperimentali dellimmunogenicità dei tumori 1. Presenza di cellule mononucleate nel siti di crescita del tumore (linfociti T, natural killer, macrofagi) 2. Iperplasia dei linfonodi drenanti il sito di crescita del tumore 3. Evidenze di effetti dovuti a citochine pro-infiammatorie direttamente sul tumore (indotta espressione di MHC II, ICAM-1) 4. Regressione spontanea di alcuni tumori.

9 Evidenze cliniche di immunosorveglianza 1)Inherited Immunodeficiency 2) Organ transplant recipients 3) Patients with auto-immune disorders 4) Second tumors in cancer patients 5) HIV infection

10 Evidenze cliniche di immunosorveglianza SyndromeImmune defectTumors X-linked immunodeficiency Impaired B cell response to EBV Non Hodginks Limphoma Wiskott-Aldrich syndrome Complex multicompartment defects NHL, Acute myeloid leukemia, Hodginks disease Common variable immunodeficiency Cellular and humoral defects NHL, stomach cancer 1) Inherited Immunodeficiency

11 Experiments in gene-knockout mice lacking various components of the immune system - IFN- deficient mice have a higher rate of both spontaneous and carcinogen- induced tumors - Double IFN- and Rag-2 deficient mice - Perforin-deficient mice - TRAIL-deficient mice Role for NK cells

12 Tumor cell recognition by NK cells Missing self recognition: - Inhibitory receptors (KIR, CD94/NKG2A) bind directly to intact MHC class I molecules Recognition of induced self ligands as marker of abnormal self: - Stimulatory receptors (NKG2D) bind to ligands expressed or up-regulated in tumor cells and virally infected cells - Ligands: MICA/B expressed on tumor cells of epithelial origin; Retinoic acid early inducible protein (Rae1); H60

13 Limmunosorveglianza presuppone lesistenza di: 1. Antigeni tumore specifici/ tumore associati 2. Cellule effettrici in grado di riconoscere il tumore e mediarne il rigetto Conoscere lidentità degli antigeni tumorali è fondamentale per sviluppare immuno-terapie antigene/tumore specifiche Caratterizzare le cellule effettrici è fondamentale per poter intervenire e manipolare la risposta immunitaria

14 Risposta primaria Tumore (sorgente di antigene) Cellule adibite alla presentazione antigenica Linfociti T e B Colocalizzazione Elementi critici nello sviluppo di una risposta anti-tumorale Risposta secondaria Tumore Cellule adibite alla presentazione antigenica Linfociti T e B Macrofagi, cellule NK, NKT

15 Anatomy of the adaptive immune responses Primary lymphoid organs: bone marrow and thymus Secondary lymphoid organs: lymph nodes and spleen Non lymphoid organs: site of infection

16 Anatomy of the adaptive anti-tumor immune responses Primary lymphoid organs: bone marrow and thymus Secondary lymphoid organs: lymph nodes and spleen Non lymphoid organs: site of tumor growth

17 Physiological condition Tissue antigens Tissue-specific antigens are ignored

18 Patological conditions Tumor-specific immune responses Tumor-specific T cells Blood Transforming event Lymph Blood Tumor antigens or tumor cells

19 Immune stimulation or inflammation Spontaneous inflammation in the tumor microenvironment Antigen-specific immunization Non specific immune stimulation Tumor growth Tumor regression Tumor progression The fine balance between immune responsiveness and immune resistance

20 Critical factors in adaptive immune responses Proper selection of antigen specific progenitors Secondary lymphoid organs Appropriate timing Proinflammatory stimuli Shaping of the immune response over time and space

21 Th-1 CD4 T lymphocytes: helper cell, CD8, APC, killing Th-2 CD4 T lymphocytes: helper cell, B cells Tc-1 CD8 T lymphocytes: cytotoxic cell B cells: Ab production NK, NKT, gd T cells Main lymphocytes subsets participating to anti-tumor responses

22 Classification of tumor antigens - Tumor-specific shared antigens/Cancer-testis antigens Antigens encoded by genes expressed in variable proportion on different cancers, but not in normal tissues except testis and placenta - Differentiation tumor antigens Antigens encoded by genes expressed in tumor cells and in normal tissue - Unique tumor antigens Antigens corresponding to peptides encoded by regions of ubiquitously expressed proteins that are mutated in tumor cells - Over-expressed tumor antigens Antigens encoded by non-mutated genes that are expressed at different level in neoplastic and normal tissue - Viral antigens Antigens derived from oncogenic viruses

23 Fong, L and Engleman, EG Annu Rev Immunol, 18:217, 2000

24 CD4+ T cells are important for tumor rejection - In vivo depletion experiments with antibody recognizing different lymphocytes population - Experiments using CD4-knockout mice - Adoptive transfer of tumor-specific CD8+ and CD4+ T lymphocytes

25 CD4 + T cells in anti-tumor immune response Lymphoid organs Peripheral tissues

26 Priming phase Effector phase CD4+ CTL CD8+ CTL Immature dendritic cell Tumor cell Draining Lymph node Tumor cell Macrophage MHC Class II MHC Class I Tumor antigens Tumor peptides Release of granule contents Mature dendritic cell CD8+ T cell CD4+ T cell Killing CD40 CD40L Killing Reactive oxigen intermediates Th2 Th1 B cell Th1/Th2

27 Effector mechanisms in cancer immunity - Antibodies - Coating with antigen, opsonization and phagocytosis by macrophages - Crosspriming - NK cells -Lyse MHC mismatched cells, cells having low level of or lacking MHC class I expression, cells expressing ligands of stimulatory receptors - NKT cells - Recognize glycolipid antigens by non-classical MHC molecules and produce large amounts of type 1 or type 2 cytokines - Macrophages and neutrophils - Activated by tumor microenvironment, and CD4+ T cells - Release of tumoricidal factors (TNF, nitrogen oxides), endocytosis of malignant cells - Cytokines - T cells

28 Different mechanisms may be responsible for failure to develop effective anti-tumor immunity in vivo - Failure to develop immunity Ignorance -Tolerance induction Anergy/Deletion - Mechanisms of immune escape

29 Tumor cell T cell Tolerance Antigen uptake by tolerance-inducing APC T cell APC Failure to develop efficient anti-tumor immunity TCR MHC-peptide Receptor for costimulatory signals

30 Mechanisms of tumor immune escape - Loss of MHC expression - Down-regulation of antigen processing machinery - Antigen loss variants - Expression of local inhibitory molecules (FasL) - Secretion of immunosuppressive cytokines - IL-10, TGF-

31 Cancer Immunotherapy

32 Strategies of antitumor immunotherapy - Adoptive immunotherapy - Active vaccination - Monoclonal antibodies -Vaccination against tumor neovascularization

33 Strategies of antitumor immunotherapy - Adoptive immunotherapy - LAK - TIL - DLI - CD8 clones - Cell cloning technique - TCR transfection

34 Adoptive transfer of IL-2 activated tumor infiltrating lymphocytes (TILs) Adoptive transfer of TILs expanded in vitro and high dose IL-2 following a non- myeloablative conditioning regimen Dudley ME et al. Science, 2002


36 Antigen specific T cells transfer

37 Adoptive transfer of antigen-specific CD8+ T cell clones Yee, C. et al. PNAS 99: 16168, 2002 In vivo persistence, migration and antitumor effect of transferred MART-1/Melan-A specific T cell

38 Strategies of antitumor immunotherapy - Monoclonal antibodies

39 Monoclonal antibodies Mechanisms of action: - antibody-dependent cell-mediated cytotoxicity - cross-presentation by immune complexes Clinical studies - anti-CD20 (B-cell lymphomas)

40 Monoclonal antibodies as magic bullets.

41 Strategies of antitumor immunotherapy - Active vaccination

42 Goal of cancer vaccines - To identify ways to break tolerance - To identify resistance mechanisms and ways to circumvent them

43 Vaccine design - Targeting CTL responses - Targeting CD4+ T cell responses - Targeting multiple antigens and epitopes that cover a broad repertoire of T cells - Choice of the antigen Undefined (cancer cell extracts, mRNA) Defined - Adjuvant - Dose - Route of injection - Schedule

44 Different forms of cancer vaccines u - Cell based cancer vaccines - Antigen specific cancer vaccines - Dendritic cells vaccines - Heat shock proteins vaccines

45 Cell-based cancer vaccines Tumor cell as a source of antigen (autologous or allogenic) Early generation: - Killed tumor cells or tumor cell lysate mixed with adjuvants such as BCG Genetically modified tumor cells: - Immunologically active genes - MHC genes - genes encoding membrane associated costimulatory molecules (B7-1, B7-2) - cytokines genes (IL-2, IL-4, GM-CSF) Clinical trials: - Several with limited success

46 Antigen-specific cancer vaccines - Peptide vaccine - Protein vaccine - Recombinant viral vaccine - Recombinant bacteria vaccine - Nucleic acid vaccine

47 Peptide vaccine Depends on loading of empty MHC class I molecules in vivo Advantages - Easy to manufacture in GMP conditions Disadvantages - May results in tolerance induction Clinical trials : - MAGE-3 presented by HLA-A1 Marchand M, et al. Int J Cancer 80:219, 1999 - gp100 presented by HLA-A2 Rosenberg SA, et al. Nat Med 4:321, 1998

48 Protein vaccine Depends on cross-priming on autologous MHC molecules Advantages - non HLA restriction - activation of both CD8+ and CD4+ T cells Disadvantages - Difficulty and expenses of generating recombinant proteins suitable for human administration

49 Recombinant viral vaccines Adenovirus, vaccinia virus, avipox Mechanisms of action: - Cellular damage, danger signals, cross-priming - Direct infection of bone marrow derived APC Disadvantages - Neutralizing antibodies - Previous exposure to cross-reacting viruses - Previous immunization Clinical trials Weak generation of anti-tumor T cells -Rosenberg SA, et al. J Natl Cancer Inst 90:1894, 1998 (Melanoma, MART-1 or gp100) -Marshall JL, et al. J clin Oncol 23: 3963, 2000 (CEA) - Eder JP, et al. Clin Cancer Res 5: 1632, 2000 (Prostate cancer, PSA)

50 Nucleic acid vaccines Advantages - easy to construct - chemical stability - inherently immunogenic, do not need adjuvants - broad range of specific immune responses - no presence of neutralizing antibodies - less risk of insertional mutagenesis - do not down-regulate MHC Disadvantages - Much less potent - No replicative amplification - Smaller inflammation - No danger response

51 Heat shock proteins gp96 and hsp70 purified from tumor cells Mechanisms of action: - Bind a wide array of peptides - They introduce bound peptide into the MHC class I and II processing pathways - Binding of gp96 to macrophages induces secretion of proinflammatory cytokines Disadvantages - Tumor tissue required Clinical trials - Belli, F. et al. J Clin Oncol 20:4169, 2002

52 Dendritic cells vaccines AAA AAA AAA AAA Apoptotic bodies LysatesmRNA Bacteria Natural or Synthetic peptides Gene Virus Vector Genetic delivery Non genetic delivery

53 Banchereau J, et al. Cancer Res. 61:6451, 2001 CD34 derived mature DC pulsed with several MHC class I tumor peptides plus KLH and Flu-MP

54 Thurner, B et al. J Exp Med 11:1669, 1999 Schuler-Thurner, B et al. J Exp Med 10:1279, 2002 Mature monocyte-derived DC pulsed with several MHC class I and class II tumor peptides plus TT

55 Ongoing Phase I or II Nonrandomized Trials of Cancer Vaccines




59 Ongoing Phase I, II, or III Randomized Trials of Cancer Vaccines


61 What we have learn from clinical trials so far - Vaccinations are safe and well tolerated - No or transient major side effect (autoimmunity phenomena) - Patients are immunized, with tumor specific T cell induction or expansion - Memory induction? - Limited clinical benefits in heavily affected patients

62 Factors limiting the therapeutic impact of anti-tumor T cells Lymphocytes factors - CD4+ and CD8+ subsets - Insufficient numbers, avidity - Secretion of non appropriate cytokines or not sufficient lytic activity - Regulatory T cells Tumor factors - Production of immunosuppressive cytokines - Loss of MHC molecules or tumor antigens

63 Future challenges - Best DC culture methods (maturation stage) - Optimum antigen loading - Most important TAA - Vaccination schedule - Dosages - Route of injection - Improvements/standardization of immunomonitoring - Combination therapy

64 Strategies of antitumor immunotherapy -Vaccination against tumor neovascularization

65 Vaccination against tumor neovascularization - DC pulsed with soluble VEGF-R2 - neutralizing antibodies - CD8+ CTL - Attenuated salmonella engineered to express VEGF-R2 - CD8+ CTL Preclinical studies

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