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TUMOR IMMUNOLOGY Attila Bacsi PhD THE BIOLOGY OF TUMORS BRIEFLY • MORE THAN 100 TUMOR TYPES • Most tumors develop later in life, mechanisms to control tumor development must exist. • 14 million new cancer cases/year worldwide /50% mortality. • Contonuous cell division in a lifetime. • Each of us carries 60 or more germline mutations not present in parents. THE HALLMARKS OF CANCER (OLD STYLE) Hanahan and Weinberg Cell, 2011 pp646- SO FAR INDEPENDENT OF THE IMMUNE SYSTEM THE HALLMARKS OF CANCER (ONE STEP FORWARD) Hanahan and Weinberg Cell, 2011 pp646- BENIGN OR MALIGNANT TUMORS SOME IMPORTANT QUESTIONS ARISE: DO IMMUNOCYTES RECOGNIZE TUMORS? DOES THE IMMUNE SYSTEM CONTROL THE DEVELOPMENT OF TUMORS? (IMMUNOSURVEILLANCE) CAN THE IMMUNE SYSTEM BE MODIFIED TO ERADICATE TUMORS? MHC-DEPENDENT REJECTION OF TUMORS INFECTIVE FACIAL TUMOR IN THE INBREAD POPULATION OF THE TASMANIAN DEVIL About 2/3 of Hungary Population half million MULTIPLE MUTATIONS LEAD TO DEVELOPMENT OF TUMORS ACTIVATION OF ONCOGENES Mitogens Growth factor receptors Secondary messengers Transcriptional activators Malignant Cell cycle genes Tissue cells cells INACTIVATION OF TUMOR SUPPRESSOR GENES Growth inhibitors Cell cycle inhibitors Programmed cell death genes DNA repair enzymes doi:10.1038/35101031 VARIOUS ONCOGENES ARE ASSOCIATED WITH DEFINED TUMORS ONCOGENE ASSOCIATED TUMORS c-erb-B2 Breast and ovarian carcinomas ras Many carcinomas and leukemias c-sis Gliomas c-abl Chronic myelogenous leukemia, acute lymphocytic leukemia c-myc Lymphomas BRCA-1 APC NF-1 Breast and ovarian carcinomas Colonic adenocarcinomas Neurofibromas and neurofibrosarcomas Rb Retinoblastomas, osteosarcomas, small cell lung carcinomas p53 Many carcinomas bcl-2 Chronic lymphocytic leukemia, lymphomas CHROMOSOMAL TRANSLOCATION IN BURKITT’S LYMPHOMA 8 c-myc 14 8q- CH VH 14q+ CH VH c-myc Uncontrolled proliferation due to the activation of cmyc oncogene. EBV induced tumor TUMOR-ASSOCIATED VIRUSES TUMOR-SPECIFIC ANTIGENS AND TUMOR ASSOCIATED ANTIGENS TUMOR-SPECIFIC ANTIGENS CT ANTIGENS Cancer/testis antigens are expressed almost entirely by cancerous cells, showing little or no expression in healthy tissue, with the exception of normal testis, embryonic ovaries and placenta. THE TUMOR-SPECIFIC IMMUNE RESPONSE DENDRITIC CELLS ARE ABLE TO ACTIVATE TUMOR-SPECIFIC T-CELLS (CROSS-PRESENTATION) DOI: 10.1126/science.1203486 WHY ARE THEN TUMORS NOT ELIMINATED? Tumors are not highly immunogenic Limited cytotoxic T-cell activity: MHCI – mutation, β2m,TAP Apoptosis: soluble Fas TGF-β: inhibition of immune response TOLEROGENIC MICROENVIRONMENT MECHANISMS OF TUMOR ESCAPE MODULATION OF DC-FUNCTION BY THE TUMOR TSLP-INDUCED DCS RECRUIT TH2 AND TREG CELLS MANIPULATION OF THE IMMUNE RESPONSE BY A TUMOR MANY TUMORS LOOSE EXPRESSION OF HLA CLASS I PROTEINS Loss of HLA class I expression in prostate cancer Class I molecules are stained brown. The stain and HLA class I molecules are not seen on the tumor mass but are restricted to lymphocytes infiltrating the tumor and tissue stromal cells. HUMAN EPITHELIAL TUMORS CAN INHIBIT THE RESPONSE OF LYMPHOCYTES EXPRESSING NKG2D TUMOR IMMUNOTHERAPY (Monoclonal antibodies) POLYCLONAL ANTIBODIES clones of many B cells polyclonal antibodies binding to multiple epitopes MONOCLONAL ANTIBODIES clones of a single B cell monoclonal antibodies binding to a single epitope POLYCLONAL ANTIBODIES Ag Immunserum Polyclonal antibody - Products of a set of B-lymphocyte clones - Heterogeneous in antigen specificity, affinity, and isotype Set of B-cells Ag Activated B-cells Antibodyproducing plasma-cells Antigen-specific antibodies MONOCLONAL ANTIBODIES (MAb) Products of clones of one B-lymphocyte Homogeneous in specificity, affinity, and isotype Can be found in humans in a pathologic condition called multiple myeloma, which is a malignant proliferation of a plasma cell (see supplementary) STEPS OF MAb GENERATION (1) Immunization of a mouse (2) Isolation of B cells from the spleen (3) Cultivation of myeloma cells (4) Fusion of myeloma and B cells (5) Separation of cell lines (6) Screening of suitable cell lines (7) in vitro (a) or in vivo (b) multiplication (8) Harvesting *For more details see supplementary SELECTION OF HYBRIDOMA CELLS Immunization Spleen B cells, *HGPRT+ Myeloma cell HGPRT- aminopterine PEG fusion HAT selection Testing supernatants for specific antibody production HAT= hypoxanthine, aminopterine, thymidine *Hypoxantine-guanine phosphoribosyltransferase FEATURES OF POLYCLONAL AND MONOCLONAL ANTIBODIES Polyclonal antibodies Monoclonal antibodies Number of recognized antigen determinants several (frequent cross-reactions) mostly one Specificity polyspecific monospecific Affinity Varying (diverse antibodies) high Concentration of nonspecific immunoglobulins high low Cost of preparation low high Standardisability Impossible (or uneasy) easy Amount limited unlimited Applicability method-dependent excellent DIFFERENT TYPES AND IMMUNOGENICITIES OF ANTIBODIES USED IN THERAPY Mouse Chimeric Human Humanized *Humanized antibodies are from non-human species whose protein sequences have been modified to increase their similarity to antibody variants produced naturally in humans (except CDR loops)! TUMOR IMMUNOTHERAPY MAIN STRATEGIES FOR CANCER IMMUNOTHERAPY Sattwa S. Neelapu Mol. Oncol (2015 in press) MONOCLONAL ANTIBODIES USED IN THE TREATMENT OF PATIENTS WITH CANCER ADCC---NK, macrophage, complement Immunotoxins MANY THERAPEUTIC ANTI-CANCER MONOCLONAL ANTIBODIES WORK BY DELIVERING THE TUMOR CELLS TO NK CELL-MEDIATED ADCC Antibodies bind to a cell-surface antigen of the tumor cells, for example CD20. The Fc regions of the antibodies engage FcγRIII on an NK cell, which then becomes activated to kill the tumor cell. ANTIBODIES ARE USED TO TARGET TOXINS TO TUMOR CELLS CHECKPOINT THERAPIES • Blocking negative receptors used by Tregs • Targeting stimulatory co-receptors with agonistic antibodies BLOCKING THE INHIBITORY EFFECTS OF CTLA4 WITH A HUMAN MONOCLONAL ANTIBODY (IPILIMUMAB ETC) 2 year survival is over 24% but quite some complications (GI). Melanoma. Clinical trials: prostate cancer, lung carcinoma Blocking the PD1/PDL1 interaction with a human monoclonal antibody also works. BLOCKING PD-1/PD-L1 INTERACTION WITH A HUMAN MONOCLONAL ANTIBODIES SIGNIFICANTLY IMPROVES THERAPY Works well for melanoma, but it is in trial for many less immunogenic tumors. Padmanee Sharma1,2 and James P. Allison SCIENCE 2015 Vol. 348 pp56 COMBINATIONAL THERAPIES MAY HELP WHEN TUMORS ARE NOT IMMUNOGENIC AZ AKTÍV TUMOR-SPECIFIKUS IMMUNTERÁPIA LEHETŐSÉGEI IMMUNOTHERAPY BY VACCINATON A tumor antigének beviteli módja Tumor proteinderived peptide Anti-idiotipe Ab Tumor protein Vírus-tumor genome Modified tumor cell Plasmid DNA Irradiated tumor cell Modified DC Tumor cell lysate Loaded DC Heat shock protein Mocellin S et al. Lancet Oncology VACCINATION AGAINST HUMAN PAPILLOMA VIRUSES CAN PREVENT CERVICAL CANCER •HPV is an oncogenic virus causing genital warts. •250000 women die of cervical cancer each year. •Almost all cervical and ovarian cancers are HPV positive. •Preventing chronic HPV infection should prevent cancer. VACCINATION OF MELANOMA PATIENTS MAY CAUSE THEIR TUMOR TO REGRESS Rec. virus Synthetic peptide vaccine It is not yet clear when the vaccine would work. Spectrum from remission to no response. ADOPTIVE TRANSFER OF DENDRITIC CELLS LOADED IN VITRO WITH TUMOR ANTIGENS ADOPTIVE T-CELL TRANSFER T-CELL RESPONSES TO TUMORS CAN BE IMPROVED WITH CHIMERIC ANTIGEN RECEPTORS (CARS) • Low affinity of TCR (compared to virus specific T cells). • MHC restriction prevents use in the entire population. • Problem solved by Fv. • Variable fragment of the heavy and light chains of a tumor-specific antibody made a single chain. • Fusion of FV to an intracellular domain containing CD28, CD137 and zeta-chain sequences. • Generates strong signal in the absence of costimulation. B-CELL TUMORS CAN BE TARGETED BY CARS SPECIFIC TO CD19 TREATMENT OF B-CELL TUMORS USING ANTI-CD19 CAR T CELLS THANK YOU FOR YOUR ATTENTION!