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Immunity and Tumors

Immunity and Tumors. Cancer Immunotherapy. 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

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Immunity and Tumors

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  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. Pathogenesis of neoplasia Promotion Normal Initiation Progression Clonal evolution Additional mutations DNA damage (chemical, phisical, biologic) DNA damage differentiation proliferation proliferation apoptosis

  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. L’immunosorveglianza • 1959 Thomas e Burnet: l’immunosorveglianza • The immune system maintains vigil over both alien microorganisms and altered somatic cells • Il tumore è antigenico ed immunogenico • 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: • L’insorgenza di tumori è piu’ alta in assenza di competenza • immunologica (immunodeficienze congenite o acquisite)

  6. Evidenze di immunogeneticità dei tumori Sarcoma Vaccinazione con cellule tumorali Resezione chirurgica Topo naive Topo vaccinato Nessuna crescita Crescita del tumore Nessuna crescita

  7. Conclusions from experiments on transplanted tumors • - 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

  8. Evidenze sperimentali dell’immunogenicità 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 • 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 1) Inherited Immunodeficiency

  11. Experiments in gene-knockout mice lacking various components of the immune system • - IFN-g deficient mice have a higher rate of both spontaneous and carcinogen- • induced tumors • - Double IFN-g 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 cellsand virally infected cells - Ligands: MICA/B expressed on tumor cells of epithelial origin; Retinoic acid early inducible protein (Rae1); H60

  13. L’immunosorveglianza presuppone l’esistenza di: 1. Antigeni tumore specifici/ tumore associati 2. Cellule effettrici in grado di riconoscere il tumore e mediarne il rigetto Conoscere l’identità 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. Elementi critici nello sviluppo di una risposta anti-tumorale Risposta primaria Tumore (sorgente di antigene) Cellule adibite alla presentazione antigenica Linfociti T e B Colocalizzazione Risposta secondaria Tumore Cellule adibite alla presentazione antigenica Linfociti T e B Macrofagi, cellule NK, NKT

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

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

  17. Physiological condition Tissue antigens Tissue-specific antigens are ignored

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

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

  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. Main lymphocytes subsets participating to anti-tumor responses 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

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

  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. Failure to develop efficient anti-tumor immunity Tumor cell Antigen uptake by tolerance-inducing APC T cell APC T cell TCR MHC-peptide Tolerance 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-b

  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

  35. Antigen specific T cells transfer

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

  37. Strategies of antitumor immunotherapy • Monoclonal antibodies

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

  39. Monoclonal antibodies as magic bullets.

  40. Strategies of antitumor immunotherapy - Active vaccination

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

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

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

  44. 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

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

  46. 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

  47. 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

  48. 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)

  49. 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

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