Immunotherapy Ivo Minárik, 2007

Immunotherapy 2 Suppress immune response Suppress immune response Encourage immune response Encourage immune response

Suppressing immune response immunosuppresive drugs – e.g. Cyclosporin, tacrolimus, corticosteroids, etc. immunosuppresive drugs – e.g. Cyclosporin, tacrolimus, corticosteroids, etc. Antibodies Antibodies Dendritic cells Dendritic cells Regulatory T cells Regulatory T cells

Antibodies Anti-lymphocyte globulin – depletion of allogenic lymphocytes before organ transplatation Anti-lymphocyte globulin – depletion of allogenic lymphocytes before organ transplatation Anti-CD3 – promising in DM1 Anti-CD3 – promising in DM1 Anti-CD4 - disappointing Anti-CD4 - disappointing

Antibodies 2 Anti-TNFα therapy (infliximab) – rheumatoid arthritis Anti-TNFα therapy (infliximab) – rheumatoid arthritis Receptor for TNFα Receptor for TNFα Receptor for IL-1 Receptor for IL-1 Antibodies against adhesion molecules (natalizumab) – block migration of lymphocytes to the site of inflammation – Crohn‘s disease, multiple sclerosis Antibodies against adhesion molecules (natalizumab) – block migration of lymphocytes to the site of inflammation – Crohn‘s disease, multiple sclerosis

Role of costimulatory molecules

Interference with costimulatory pathways CTLA4Ig – binds to CD80 and CD86 CTLA4Ig – binds to CD80 and CD86 Psoriasis Psoriasis Anti-CD40L – on surface of T cells Anti-CD40L – on surface of T cells

Immune modulation Manipulating T regulatory cells (IL-10, TGFβ), immature dendritic cells Manipulating T regulatory cells (IL-10, TGFβ), immature dendritic cells

Dendritic cells TLR receptors (Toll-like) – essential for the initiation of immune response TLR receptors (Toll-like) – essential for the initiation of immune response If no TLR costimulation – Tcell anergy, expansion of regulatory T cells If no TLR costimulation – Tcell anergy, expansion of regulatory T cells

Allergy Hyposensitization – repeated application of gradually growing doses of allergen Hyposensitization – repeated application of gradually growing doses of allergen Lasts for 3-5 years Lasts for 3-5 years Isotype switch, degranulation of mast cells Isotype switch, degranulation of mast cells Subcutaneous, inhalation, ingestion Subcutaneous, inhalation, ingestion

Encouraging immune response Cancer therapy – nonspecific (IL-2, IFNa) × specific Cancer therapy – nonspecific (IL-2, IFNa) × specific Tumor cells – lower expression of MHC I, production of IL-10, TGFβ, VEGF, frequent mutations Tumor cells – lower expression of MHC I, production of IL-10, TGFβ, VEGF, frequent mutations

Antibodies Ab+cytotoxic drug/radioisotope/toxin – difficult to asign appropriate antigen for targeting Ab+cytotoxic drug/radioisotope/toxin – difficult to asign appropriate antigen for targeting Disappointing – antigen instability, inefficient killing, inefficient penetration Disappointing – antigen instability, inefficient killing, inefficient penetration Especially used for lymphomas and leukemias Especially used for lymphomas and leukemias

Antibodies 2 Targeting growth factors + other molecules Targeting growth factors + other molecules Bevacizumab (VEGF) – colon cancer, renal cancer Bevacizumab (VEGF) – colon cancer, renal cancer rituximab (anti CD20) – non-Hodgking lymphoma rituximab (anti CD20) – non-Hodgking lymphoma

Strategy to enhance Tcell immunity Antigens + adjuvant (GM-CSF, extract from Corynebac.parvum, CpG) Antigens + adjuvant (GM-CSF, extract from Corynebac.parvum, CpG) Dendritic cells – antigens in the form of peptide (HLA restriction),cDNA, RNA, necrotic or apoptotic cells Dendritic cells – antigens in the form of peptide (HLA restriction),cDNA, RNA, necrotic or apoptotic cells TILs (tumor infiltrating lymphocytes) TILs (tumor infiltrating lymphocytes) Adoptive cell transfer Adoptive cell transfer