DNA vaccine induces T H 1 response. CpG plasmid APC TLR9 IL12 T H 1 CTL IgG2a B cell DNA vaccine is preferred for inducing immunity against intracellular infection. pXL2 (RSV DNA vaccine): T H 1 response pXL0 (control) Live RSV vaccine: balanced T H 1/T H 2 Formalin inactivated RSV: T H 2 response
DNA vaccine expressing multiple antigens DNA vaccine priming / boosting with other vaccines
Mucosal vaccine Mucosal surface is the major site of pathogen entry. Mucosal vaccine induces both mucosal and systemic immunity. Injected vaccines are poor inducers of mucosal immunity. DC M B GC T T Plasma cells, memory B cells T H cells, CTL
Mucosal lymphocytes home to mucosal tissues. Peyer’s patch Plasma cells, CTL, T H cells Memory cells Lymph node Blood circulation Blood circulation Other mucosal tissues Other mucosal tissues Inductive site Effector site Effector site Common mucosal immune system
Lymphocyte homing to mucosal tissue Mucosal tissue-specific adhesion molecules and chemokine/chemokine receptors plasma cells CCR10 CCL28 Epithelial cells of intestine and other mucosal tissues 4 7 integrin Endothelial cells of venules in intestine MADCAM1 (addressin) CCR9 CCL25 Epithelial cells of intestine and other mucosal tissues 4 7 integrin Endothelial cells of venules in intestine MADCAM1 (addressin) Effector T cells Mucosal induction site Mucosal effector site
Mucosal immunization also induces systemic immunity. DC M B GC T T Mucosal lymphoid tissue Lymph node Systemic immunity Mucosal immunity
Mucosal plasma cells produce IgA. Epithelial cells Mucus Dimeric IgA Neutralization IgA + Mucosal plasma cells IgG Systemic immunity (lymph nodes, spleen) Blood circulation Blood circulation Mucosal effector T and B cells CTL T H IgA > IgG IgG > IgA
Preferential localization of mucosal immunity to induction site
Challenges in mucosal vaccine Degradation, dilution on mucosal surface Live attenuated pathogen (polio vaccine, S. typhi vaccine) Use as recombinant vectors vaccines Prevent tolerance Mucosal adjuvant to induce “danger signal” (activate DCs) Mutated enterotoxins of bacteria (e.g. cholera toxin) PAMPs (e.g. CpG, flagellin)
Immune response against tumor Tumor cells Tumor Ag Uptake of Tumor Ag By immature DCs Mature DCs MHC I and II-antigen B7 CD4 T CD8 T CTL CTL Kill tumor cells Lymph node Cancer vaccine
Boosting Immune response against tumor Tumor cells Tumor Ag Uptake of Tumor Ag By immature DCs Mature DCs MHC I and II-antigen B7 CD4 T CD8 T CTL CTL Kill tumor cells Lymph node Immunization with Tumor Ag Loading DCs with Tumor Ag (DC vaccine) In vitro activation of anti-tumor T cells Adoptive transfer Cytokine stimulation
Dendritic cell vaccine patient monocytes Immature DCs CD34 + HSC Direct isolation Mature DCs Cytokines DC loaded with tumor Ag Peptides or proteins (tumor Ag) Tumor cell lysate cytokines cytokines
Cancer vaccine trials Peptide vaccines alone or with IL-12 or GM-CSF Recombinant virus expressing tumor antigens Irradiated autologous tumor cells or tumor cell lysates Dendritic cells loaded with peptides, proteins, or tumor lysates, etc.
Immunosuppression mechanisms of tumor HSC Inhibition of DC maturation CMP iMC Immature Myeloid cells myeloid DCs M granulocyte Immature DC activation Mature DC Bone marrow Peripheral tissues
Immature DCs capture antigens. Mature DCs activate T cells. Immature DC Mature DC MHC II - B7 - MHC I + MHC I + MHC II + B7 + Antigen capture Antigen presentation CD4 T CD8 T T H CTL 2 o lymphoid tissues T cell tolerance T cell activation
Tumors inhibit DC maturation. Immature DC Mature DC MHC II - B7 - MHC I + MHC I + MHC II + B7 + Tumor cells VEGF M-CSF IL6 Cyclooxygenase-2 (COX2) produces prostaglandin E2, PGE2) VEGF (vascular endothelial growth factor) M-CSF (macrophage colony-stimulating factor) PGE2 IL10 TGF- gangliosides Tumor microenvironment
Reduced number of DCs in cancer patients Clinical Cancer Research 6, 1755-1766 (2000) HNSCC: head and neck cancer
Defective DC function in cancer patients DCs (mismatched class II MHC) CD4 T cells Proliferation ( 3 H incorporation)
Cancer patients have higher proportions of Immature DCs. Immature DCs: HLA-DR - (class II MHC) B7 - CD40 -
Surgery removal of tumor reduces immature DCs. 5 patients Proportion of immature DCs
Reduction of immature DCs after chemotherapy and Anti-VEGF antibody treatment.
Tumors induce the expression of B7-H1, H4 in APCs. Normal maturation B7.1(CD80), B7.2(CD86) T cell activation B7-H1, H4 Tumor microenvironment B7-H1, B7-H4 inhibit T cell activation (co-inhibitory molecules) Some tumor cells express B7-H1,B7-H4. B7-H1,B7-H4
CD4 + CD25 + FoxP3 + T cells (5-10% of peripheral CD4 T cells) Cancer patients have higher levels of T reg cells. Inhibit T cell response.
Depletion of CD25 + cells increases tumor rejection.
Depletion of T reg cells by DAB 389 IL-2 (denileukin diftitox, ONTAK) High affinity IL2 receptor IL2R : CD25 Low affinity IL2 receptor Naive T cell Effector T cell CD4 + CD25 + T reg CD25 + T cell IL2 Diphtheria toxin DAB 389 IL-2 CD25 - T cell DAB 389 IL-2 preferentially kill CD25 + T cells.
DAB preferentially kills CD25 high T reg cells. CD4 + CD25 neg CD4 + CD25 int CD4 + CD25 high CD4 + CD25 neg T cells: naïve resting T cells CD4 + CD25 int T cells: activated T cells CD4 + CD25 high T cells: T reg cells (FoxP3 + ) J. Clinical Investigation 115, 3623-3633 (2005) RCC: Renal cell carcinoma Donor: healthy control Cancer patients have highly levels of CD25 + T reg cells (FoxP3 + )
Depletion of CD25 + T reg cells enhances T cell response against tumor. patient Vaccinated with DC vaccine against RCC Determine the frequency of CD8 + T cells that express IFN- in response to tumor. Patient Treat with DAB
Treatment with CTLA4-specific antibody CD4 + CD25 + T reg cells constitutively express CTLA4. CTLA4 antibodies improve tumor rejection, but cause autoimmunity.
Adoptive transfer of anti-tumor T cells Science 298, 850-854 (2002) 13 Cancer Patients (metastatic melanoma) Melanoma Tumor cells TIL (tumor infiltrating Lymphocyte) Expansion of TIL in cell culture Anti-CD3+IL2 These T cells can be activated By tumor antigens in self-MHC Lymphodepleted patients Cyclophosphamide fludarabine Infusion of anti-tumor T cell with IL2 6/13 responded 5/13 have autoimmune melanocyte destruction Tumor regression after a few month
Relevant part in book Cancer vaccine and therapy: page 511-520
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