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Immunotherapy Web Presentation


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Immunotherapy Web Presentation

  1. 1. Immunotherapy of Patients with Cancer Therapeutic Vaccines Presentation for January 1, 2009 Anthony E. Maida, III, Doctoral Candidate, MA, MBA Founder, Chairman and Chief Scientific Officer UC Davis Cancer Center University of California Davis Medical Center Department of Internal Medicine
  2. 2. “ A new scientific truth is not usually presented in a way that convinces its opponents … rather the opponents gradually die off, and a rising generation becomes familiar with the truth from the start.” Max Plank
  3. 3. Anthony E. Maida, III <ul><li>Formal Education </li></ul><ul><ul><li>Doctoral Candidate – Tumor Immunology </li></ul></ul><ul><ul><li>BA – History, BA – Biology, MA – Toxicology, MBA </li></ul></ul><ul><li>Professional Positions </li></ul><ul><ul><li>Formerly </li></ul></ul><ul><ul><li>VP Finance, CFO – Lockheed DataPlan, Inc. </li></ul></ul><ul><ul><li>Senior Financial Controller – Lockheed Missiles and Space Co. </li></ul></ul><ul><ul><li>Chairman – BioConsul Drug Development Corporation </li></ul></ul><ul><ul><li>Principle – Anthony E. Maida, III Consulting </li></ul></ul><ul><ul><ul><li>VCs. Hedge Funds, Pharma, Investment Banks </li></ul></ul></ul><ul><ul><li>President – CancerVax Corporation -$30 M </li></ul></ul><ul><ul><li>CEO and President - Replicon, Inc. - $3 M </li></ul></ul><ul><ul><li>CEO – Trellis Bioscience, Inc. - $ 7 M </li></ul></ul><ul><ul><li>President and CEO – Jenner Biotherapies, Inc. $ 19 M </li></ul></ul><ul><ul><li>Related financings ~ $100 N </li></ul></ul><ul><li>Professional Memberships </li></ul><ul><ul><li>ASCO, AACR, ASI, ACS, SNO, iSBTc </li></ul></ul><ul><li>Public Board Seats </li></ul><ul><ul><li>Spectrum Pharmaceuticals, Inc. (SPPI) </li></ul></ul><ul><ul><li>Sirion Therapeuitics, Inc. </li></ul></ul><ul><ul><li>Private Companies </li></ul></ul>
  4. 4. General Comments <ul><li>Cancer – Loss of Control in Cell Division; not necessarily rapid cell division </li></ul><ul><li>10 Million New Cases World-Wide Annually </li></ul><ul><li>Within 20 Years the Incidence Will Double to 20 Million </li></ul><ul><li>Leading to 6 Million Deaths </li></ul><ul><li>Major Cancers: Prostate, Breast, Lung, Colorectal, Lymphomas Etc. </li></ul><ul><li>More Than 400 Products in Various Stages in Development Today </li></ul>
  5. 5. Therapeutic Approaches <ul><li>Surgery </li></ul><ul><li>Radiotherapy </li></ul><ul><ul><li>Gamma knife </li></ul></ul><ul><li>Radio-Immunotherapy </li></ul><ul><li>Chemotherapy </li></ul><ul><li>Hormone therapy </li></ul><ul><li>Antisense </li></ul><ul><li>Gene therapy </li></ul><ul><li>Cytokines </li></ul><ul><li>Immunotherapy </li></ul><ul><ul><li>Active </li></ul></ul><ul><ul><li>Passive </li></ul></ul>
  6. 6. Surgery <ul><li>Traditional surgical approaches </li></ul><ul><li>Cryosurgery </li></ul><ul><li>Virtual surgery </li></ul><ul><li>Gamma Knife </li></ul>
  7. 7. Therapeutic Approaches <ul><li>Chemotherapy </li></ul><ul><ul><li>Alkylating Agents – C hlorabucin, Paraplatin </li></ul></ul><ul><ul><li>Anti-Metabolites – Fludara, Gemcitabine, Methotrexate </li></ul></ul><ul><ul><li>Topoisomerase Inhibitors – A driamycin, Camptosar </li></ul></ul><ul><ul><li>Microtubule Inhibitors – V incristine, Taxotere </li></ul></ul><ul><ul><li>Telomerase Inhibitors – GRN163, G4T405 </li></ul></ul><ul><ul><li>Tyrosine Kinase Inhibitors - Sunitinib®, Sarafinib® </li></ul></ul><ul><ul><li>Oncogene/Cell Signaling/Tumor Suppressors </li></ul></ul><ul><ul><li>Anti-Angiogenesis – Avastin, Neovastat, Angiozyme </li></ul></ul>
  8. 8. Therapeutic Approaches <ul><li>Immunotherapy </li></ul><ul><ul><li>Passive – Antibody Therapy </li></ul></ul><ul><ul><ul><li>Herceptin – Her2/Neu, Breast Cancer </li></ul></ul></ul><ul><ul><ul><li>Avastin - anti-VEGF </li></ul></ul></ul><ul><ul><ul><li>Rituxan – anti-CD20, NHL </li></ul></ul></ul><ul><ul><ul><li>Campath – anti-CD52, CLL </li></ul></ul></ul><ul><ul><ul><li>Mylotarg – anti-CD33, AML </li></ul></ul></ul><ul><ul><ul><li>Erbitux – anti-EGFr, Refractory Colorectal Cancer (Filed) </li></ul></ul></ul><ul><ul><ul><li>Various Antibodies For Imaging </li></ul></ul></ul><ul><ul><li>Active </li></ul></ul><ul><ul><ul><li>Specific </li></ul></ul></ul><ul><ul><ul><li>Non-Specific </li></ul></ul></ul>
  9. 9. Active Immunotherapy <ul><li>Vaccines </li></ul><ul><ul><li>Whole Cell Vaccines Autologous/Allogeneic </li></ul></ul><ul><ul><li>Oncolysates – Lysed Tumor Cells (Vaccinia) </li></ul></ul><ul><ul><li>Shed Tumor Antigens – Collected and Purified </li></ul></ul><ul><ul><li>TAA – Tumor Associated Antigens, Tumor Specific (p53, Ras), Tissue Specific (PSA, PSMA, PAP), Heat Shock Proteins </li></ul></ul><ul><ul><li>DNA Vaccines </li></ul></ul><ul><ul><li>Viral/Bacterial Vectors </li></ul></ul><ul><ul><li>Dendritic Cell Vaccines – Pulsed With Peptide, lysate </li></ul></ul><ul><ul><li>Fusion of Autologous Dendritic Cells With Tumor Cells </li></ul></ul>
  10. 10. Active Immunotherapy <ul><li>Whole Cell Vaccines </li></ul><ul><ul><li>Autologous/Allogeneic - Whole Tumor Cell </li></ul></ul><ul><ul><ul><li>Polyvalent Vaccines </li></ul></ul></ul><ul><ul><ul><li>Dead, Apoptotic, Mechanically Disrupted or Irradiated Cells </li></ul></ul></ul><ul><ul><ul><li>Transduced or Transfected With Various Genes, Co-Stimulatory Molecules, GMCSF </li></ul></ul></ul><ul><ul><ul><li>DNP Hapten-modified Melanoma Cell Vaccine </li></ul></ul></ul><ul><ul><ul><li>Usually Combined With Adjuvants for Up regulation of Costimulatory Molecules or ‘Danger Signals’ (P. Matzinger) </li></ul></ul></ul><ul><ul><ul><li>Transduced With Allogeneic MHC Genes </li></ul></ul></ul>
  11. 11. Active Immunotherapy <ul><li>Recombinant Viruses </li></ul><ul><ul><li>Vaccinia, Canarypox (ALVAC), Fowlpox, Adenovirus </li></ul></ul><ul><ul><li>Able to Induce Strong Humoral and Cell Mediated Responses </li></ul></ul><ul><ul><li>Insert cDNA Encoding Various Antigens or Peptides, Cytokines </li></ul></ul><ul><ul><li>However </li></ul></ul><ul><ul><ul><li>Recombination to Virulent Form </li></ul></ul></ul><ul><ul><ul><li>Viremia in Immunosuppressed Individuals </li></ul></ul></ul><ul><ul><ul><li>Difficult to Immunize Repeatedly Due to Neutralizing Antibodies (Prime/Boost) </li></ul></ul></ul>
  12. 12. Active Immunotherapy <ul><li>Classification of Antigens </li></ul><ul><ul><li>TAA - Expressed for Example on Melanoma Cells, Normal Melanocytes and Retina but Upregulated on Tumor Cells Versus Normal, TAA, Onco-fetal </li></ul></ul><ul><ul><ul><li>Non-mutated Shared Antigens (Vitiligo) </li></ul></ul></ul><ul><ul><li>Cancer/Testis Antigens </li></ul></ul><ul><ul><ul><li>MAGE, BAGE, GAGE, NY-ESO, and RAGE, Silent in a Large Panel of Healthy Adult Tissues, With the Exception of Testis and Placenta (No MHC1 Presentation on Spermatogonia (Tumor Specific?) </li></ul></ul></ul><ul><ul><li>Tumor Specific Antigens – Cyclin-dependent Kinase CDK4 (Point Mutation), Mutant EGF, p53 </li></ul></ul>
  13. 13. Active Immunotherapy <ul><li>Vaccines against viruses known to predispose to cancer </li></ul><ul><ul><li>Hepatitis B – Hepatocellular Carcinoma </li></ul></ul><ul><ul><li>Hepatitis C – Hepatoma </li></ul></ul><ul><ul><li>EBV – Burkitt’s Lymphoma </li></ul></ul><ul><ul><li>Human Papilloma Virus (HPV), Cervical Cancer (E6 and E7) – Merck’s Gardisil® </li></ul></ul><ul><ul><li>Helicobacter Pylori – B Cell Gastric Lymphoma and Gastric Carcinoma (Gastrimmune™) </li></ul></ul>
  14. 14. Active Immunotherapy <ul><li>Full Native Protein vs Peptides </li></ul><ul><ul><li>Peptides – Poor Immunogenicity, Monospecificity, HLA Restricted, </li></ul></ul><ul><ul><li>In an Outbred Population T-cells From Individuals Express Different MHC </li></ul></ul><ul><ul><li>Full Native Sequence – One Size Fits All, off the Shelf, Let the Various APCs Select the Dominant Epitopes </li></ul></ul><ul><ul><li>Peptides very easy ad inexpensive to make vs recombinant technology. </li></ul></ul>
  15. 15. Active Immunotherapy <ul><li>DNA Vaccines </li></ul><ul><ul><li>Direct Inoculation of Plasmids, IM Best Response </li></ul></ul><ul><ul><li>‘ Gene Gun’ DNA Coated Gold Particles, </li></ul></ul><ul><ul><li>Once Inside Cell, the Plasmid Is Able to Translocate Through the Nuclear Membrane </li></ul></ul><ul><ul><li>Transduction of Various Cytokines Within Autologous Tumor, or Cultured and Re-infused </li></ul></ul><ul><ul><li>However Lack the Amplification and Generation of ‘Danger’ Signals That Can Be Elicited Via Viral or Bacterial Vectors/Vaccines </li></ul></ul>
  16. 16. Active Immunotherapy <ul><li>Recombinant Viral Vectors </li></ul><ul><ul><li>Vaccinia, Canarypox (ALVAC), Fowlpox, Adenovirus, Sindbis, Herpes Simplex Virus (HSV), Newcastle Disease Virus, Reovirus </li></ul></ul><ul><ul><li>Able to Induce Strong Humoral and Cell Mediated Responses </li></ul></ul><ul><ul><li>Insert cDNA Encoding Various Antigens or Peptides, Cytokines </li></ul></ul><ul><ul><li>However </li></ul></ul><ul><ul><ul><li>Might Recombine to Virulence </li></ul></ul></ul><ul><ul><ul><li>Viremia in Immunosuppressed Individuals </li></ul></ul></ul><ul><ul><ul><li>Difficult to Immunize Again Due to Neutralizing Antibodies (Prime/Boost) </li></ul></ul></ul>
  17. 17. Active Immunotherapy <ul><li>Bacterial Vectors </li></ul><ul><ul><li>Suitable for Recombinant Engineering </li></ul></ul><ul><ul><li>Salmonella </li></ul></ul><ul><ul><li>Listeria Monocytogenes </li></ul></ul><ul><ul><li>Attractive for Enteric Route of Administration </li></ul></ul><ul><ul><li>Endogenous Processing Through Infection of APCs </li></ul></ul>
  18. 18. Active Immunotherapy <ul><li>Dendritic Cell Therapy </li></ul><ul><ul><li>Immunize Pulsed With Peptide, but Short Half-Life, or Incubate DC With Whole Antigen, Thus Addressing HLA Restriction </li></ul></ul><ul><ul><li>Transfect/Transduce DCs With Ag Or Gene Insert Using Viral Vectors </li></ul></ul><ul><ul><li>Re-Infused Into Patients </li></ul></ul><ul><ul><li>Hybridomas Creating an APC Full of Tumor Ag </li></ul></ul><ul><ul><li>Provenge – Dendreon </li></ul></ul><ul><ul><ul><li>Autologous Dendritic Cells Pulsed With PAP Then Re-infused Into the Patient. </li></ul></ul></ul><ul><ul><li>CDVax-Brain (DCVax-L/DCVax-Prostate </li></ul></ul><ul><ul><ul><li>Autologous DC vaccine – tumor lysate/PSMA </li></ul></ul></ul>
  19. 19. Active Immunotherapy <ul><li>Heat Shock Peptide Complexes </li></ul><ul><ul><li>Intended to Generate an Immune Response to the Peptides Bound and Not to the HSP Itself HSP70/HSP96 </li></ul></ul><ul><ul><li>May Be an Important Source of Tumor Antigen for Process </li></ul></ul><ul><ul><li>Supply the Necessary ‘Danger’ Signal, Triggering DC Maturation and Processing </li></ul></ul>
  20. 20. Active Immunotherapy <ul><li>Formulation </li></ul><ul><ul><li>Liposomes </li></ul></ul><ul><ul><li>Lipid Tails </li></ul></ul><ul><ul><li>Emulsions – Oil in Water, Water in Oil </li></ul></ul><ul><ul><li>ISCOMS </li></ul></ul><ul><ul><li>Microspheres </li></ul></ul><ul><ul><li>KLH Conjugated, Other Conjugates </li></ul></ul><ul><ul><li>Alum (Also an Adjuvant) </li></ul></ul>
  21. 21. Active Immunotherapy <ul><li>Adjuvants (Non-Specific Stimulation) </li></ul><ul><ul><li>BCG – (Bacillus Calmette-Guerin) First-line Therapy of Superficial Bladder Cancer, Cell-wall Skeletal Fraction of M. Bovis, up Regulates CD83 (Maturation Marker), CD80 and CD86 in APCs </li></ul></ul><ul><ul><li>LPS (Lipid A) </li></ul></ul><ul><ul><li>Freund’s Complete (Heat Killed Mycobacteria in Mineral Oil) </li></ul></ul><ul><ul><li>Alum </li></ul></ul><ul><ul><li>Glucan </li></ul></ul><ul><ul><li>Ag Linked to KLH (Keyhole Limpet Hemocyanin) Carrier Protein </li></ul></ul><ul><ul><li>Saponin (QS21) </li></ul></ul><ul><ul><li>Toll like receptor ligands </li></ul></ul>
  22. 22. Active Immunotherapy <ul><li>Adjuvants (Non-Specific Stimulation continued) </li></ul><ul><ul><li>Various Cytokines (TNF- α , IL-1, IL-2, IL-4, IL-6, IL-7, IL-10, IL-12, GM-CSF, INF- γ , INF- α (Intron A™ - Very Toxic Grade 3 Toxicity, Hepatotoxic) – Sometimes Perfused to Limit Toxicity in Such Organs As Liver, Limb, Etc. </li></ul></ul><ul><ul><li>‘ Danger Signal’ bacterial or viral products </li></ul></ul><ul><ul><li>DETOX – Detoxified Lipid A </li></ul></ul><ul><ul><li>MDP and MDP Derivatives (MPT-PE) </li></ul></ul><ul><ul><li>TDM - Trehalose-Dimycolates (Nocardia and Corynebacteria) </li></ul></ul><ul><ul><li>CpG (Mycobacterial Adjuvants) – TLR9 MØ and DC </li></ul></ul><ul><ul><li>Picibanil – OK 432 Lyophilized Preparation of Inactivated Streptococcus Pyogenes </li></ul></ul><ul><ul><li>Propionibacterium Avidum – OK 42 </li></ul></ul>
  23. 24. Adoptive Therapy <ul><li>Transfer of Cytokines – INF- α , IL-12, IL-2, IL-4, GM-SF, INF- γ </li></ul><ul><ul><li>TNF- α and IFN- γ Reduced Activation α V β 3 Integrin Disrupting Tumor Vascularization </li></ul></ul><ul><li>Infusion and Expansion of Effector Cells </li></ul><ul><ul><li>Transfer of Lymphocytes </li></ul></ul><ul><ul><li>MØ Expanded in Vitro w/ INF- γ , MTP-PE, Other MØ Activators </li></ul></ul><ul><ul><li>TILs – Tumor Infiltrating Lymphocytes (CD4+/CD8+) Expanded w/ IL-2, Rosenberg, S.A. (NCI), Frequent Toxicity Such As Hypotension, Dyspnea and Pericarditis </li></ul></ul><ul><ul><li>LAK Cells– Lymphokine Activated Killer Cells Harvested From Peripheral Blood and Activated With IL-2 in Vitro </li></ul></ul>
  24. 25. Tumor Evasion – ‘Tumor Escape’ <ul><li>Tolerance – a lesson from CancerVax </li></ul><ul><ul><ul><li>Tolerizing DC </li></ul></ul></ul><ul><ul><ul><li>Myeloid derived suppressor cells </li></ul></ul></ul><ul><ul><ul><li>Tumor microvesicles </li></ul></ul></ul><ul><ul><ul><li>CD4+CD25+ Regulatory T cells </li></ul></ul></ul><ul><ul><ul><li>T Suppressor Cells </li></ul></ul></ul><ul><li>Tissue Localization/Sequestration (CNS/EYE/TESTES) </li></ul><ul><li>Shedding of Tumor Ags (decoys) </li></ul><ul><li>Antigenic Drift </li></ul><ul><li>Lack of Expression of Co-stimulatory Molecules </li></ul><ul><li>Decreased expression of MHC I molecules </li></ul><ul><li>Tumors and/or DCs that Secrete Immunosuppressive Cytokines (TGF- β and IL-10) </li></ul><ul><li>Expression of Fas-L on Tumor Cells </li></ul><ul><li>Modulation of Signal Transduction </li></ul><ul><ul><ul><li>Zeta Chain </li></ul></ul></ul><ul><ul><ul><li>P56lck </li></ul></ul></ul><ul><ul><ul><li>NF-k β </li></ul></ul></ul><ul><ul><ul><li>BRAF-MAPK (JEM, Vol. 203, No.7, July 10, 2006, 1651-1656) </li></ul></ul></ul><ul><li>Expression of CD55 (DAF) </li></ul><ul><li>PD-L1 (B7-H1) p Programmed Death Receptor Ligand (Decrease in TCR-mediated proliferation) </li></ul><ul><li>Interference with Apoptotic Pathways </li></ul><ul><li>Secretion of Prostaglandins – a complex role </li></ul><ul><li>Immunoediting – Immunoselection </li></ul><ul><li>Down Regulation of Adhesion Molecules (ICAM- 1/2) </li></ul><ul><ul><ul><li>Ganss et al, Cancer Research 62, 1462-1470, March 1, 2002 </li></ul></ul></ul><ul><li>Down Regulation or Modulation of Membrane Bound Ags </li></ul><ul><li>Down Regulation of TAP 1 and 2 </li></ul><ul><li>The Lack of ‘Danger Signals’ Dr. Polly Matzinger </li></ul>
  25. 26. So what is the therapy? <ul><li>Prime the patient </li></ul><ul><ul><li>For the most part SC, ID or IM </li></ul></ul><ul><ul><li>Volume of about a ml maybe more </li></ul></ul><ul><ul><li>One injection in one or more extremity </li></ul></ul><ul><ul><li>Once a month for 6 months and followed by a ‘boost’ every other month or so for six months or so. </li></ul></ul><ul><ul><li>Follow the patents immune response </li></ul></ul><ul><ul><li>Out patient basis, stick around for 20 minutes or so. </li></ul></ul><ul><ul><li>No serious sides effects – Autoimmunity? </li></ul></ul>
  26. 27. What are the Concerns? <ul><li>Autoimmunity </li></ul><ul><ul><li>‘ Vitiligo’ – Anti-CTLA-4 </li></ul></ul><ul><ul><li>‘ Blindness’ in rare cases - but reversible </li></ul></ul><ul><ul><li>Is there a basis for concern: ‘Paraneoplastic Neurological Syndrome’ </li></ul></ul><ul><li>HLA Class Restriction </li></ul><ul><ul><li>Need to address the commercial needs of industry </li></ul></ul><ul><li>Clinical Efficacy ?? </li></ul>
  27. 28. Basic Immunology <ul><li>Innate Immune Response </li></ul><ul><ul><li>1 st line of defense </li></ul></ul><ul><ul><li>Invariant </li></ul></ul><ul><ul><li>Limited in its repertoire </li></ul></ul><ul><ul><li>Constant </li></ul></ul><ul><ul><li>Very quick response </li></ul></ul><ul><li>Adaptive Immune Response </li></ul><ul><ul><li>Slow response </li></ul></ul><ul><ul><li>Highly variable </li></ul></ul><ul><ul><li>High specificity </li></ul></ul><ul><ul><li>Improves </li></ul></ul><ul><ul><li>Huge diversity </li></ul></ul>
  28. 29. Basic Immunology <ul><li>Innate Response </li></ul><ul><ul><li>Neutrophils, eosinophils, basophils (granulocytes or PMNs) </li></ul></ul><ul><ul><li>NK cells (Natural killer cells) </li></ul></ul><ul><ul><li>Mast cells </li></ul></ul><ul><ul><li>Dendritic cells- link to adaptive immunity </li></ul></ul><ul><ul><li>Macrophages (phagocytic cell, along with neutrophils) </li></ul></ul><ul><ul><li>Complement </li></ul></ul><ul><li>Adaptive Response – Specific Response </li></ul><ul><ul><ul><li>T Cells </li></ul></ul></ul><ul><ul><ul><ul><li>T Helper Cells CD4+ (TH1 and TH2) </li></ul></ul></ul></ul><ul><ul><ul><ul><li>Cytolytic T Cells (CTLs) CD8+ </li></ul></ul></ul></ul><ul><ul><ul><li>B Cells </li></ul></ul></ul><ul><ul><ul><ul><li>Antibody </li></ul></ul></ul></ul><ul><ul><ul><ul><li>ADCC </li></ul></ul></ul></ul>
  29. 30. Basic Immunology – Effector Cells
  30. 31. Basic Immunology - Complement
  31. 32. Basic Immunology – The Lymph Node
  32. 33. Immunotherapy of Cancer <ul><li>Active Immunotherapy </li></ul><ul><ul><li>Specific Stimulation – Vaccines </li></ul></ul><ul><ul><li>Non-Specific Stimulation – Adjuvant Therapy </li></ul></ul><ul><li>Passive Immunotherapy </li></ul><ul><ul><li>MAb, cytokines </li></ul></ul><ul><li>Adoptive Therapy </li></ul><ul><ul><li>Transfer of Lymphocytes Expanded With Cytokines </li></ul></ul><ul><li>Restorative Therapy </li></ul><ul><ul><li>Restore Deficiencies </li></ul></ul><ul><li>Cytomodulatory Therapy </li></ul><ul><ul><li>Enhance MHC Expression on Tumor Cells </li></ul></ul>
  33. 34. Active Immunotherapy <ul><li>TAAs </li></ul><ul><ul><li>gp100/gp75 – Differentiation Antigens Over Expressed in Malignancy </li></ul></ul><ul><ul><li>Tyrosinase – Involved in Melanin Synthesis, Over Expressed </li></ul></ul><ul><ul><li>Mart-1 – Over Expressed </li></ul></ul><ul><ul><li>MAGE-1 – MAGE-3, (Melanoma AntiGEn), BAGE, GAGE , 48% Positive for MAGE-1 and 70% for MAGE 2 or 3 </li></ul></ul><ul><ul><li>CEA – Carcinoembryonic Antigen, Over-expressed </li></ul></ul><ul><ul><li>PSMA, PSA (Tissue Specific) </li></ul></ul><ul><ul><li>GD2/GM2 – Livingston, P. </li></ul></ul><ul><ul><li>GD3 – BEC-2 Imclone </li></ul></ul><ul><ul><li>Sialyl Tn – Theratope, Breast Cancer, KLH Conjugate </li></ul></ul><ul><ul><li>KSA – 17-1A Colorectal Cancer </li></ul></ul><ul><ul><li>Her-2/neu – Tyrosine Kinase, Over-Expressed on Tumor </li></ul></ul><ul><ul><li>TRP-1, TRP-2 </li></ul></ul><ul><ul><li>MUC-1, Mucins – High Molecular Weight Glycoproteins, Tandem Repeats, Aberrant Glycosylation (Hypoglycosylation) Leads to Exposure of Novel Core Epitopes </li></ul></ul>
  34. 35. Active Immunotherapy <ul><li>How Are TAAs Identified? </li></ul><ul><ul><li>TAA – Tumor Associated Antigen – Recognized by cDNA Expression Libraries With CTLs Reactive Against Melanoma, Individual cDNA Clones Isolated on Basis of Their Ability to Stimulate Cytokine Release From Specific CTLs After Transfection Into COS-7 Cells or Other Appropriate Targets </li></ul></ul><ul><ul><li>Direct Isolation and Sequencing of Peptides/Proteins Eluted From Tumor Cells </li></ul></ul>
  35. 36. Coley’s Toxins/Mixed Bacterial Vaccine <ul><li>William Coley, M.D. (1862 – 1936) </li></ul><ul><li>1888 Dr. Coley Observed Tumor Regressions in Certain Patients Injected With an Admixture of Bacterial Toxins – Now Known As LPS </li></ul><ul><li>This Admixture Consisted of Streptococcus Pyogenes and Serratia Marcesens </li></ul><ul><li>The Concept of Using Tumor Cells for Therapy to at Least the 17 th Century </li></ul>
  36. 37. Passive Immunotherapy <ul><li>Exogenously Produced Antibodies </li></ul><ul><ul><li>Fc Receptor Mediated Cytotoxicity, ADCC/NK or Disruption of Receptor Binding/Initiation </li></ul></ul><ul><ul><li>Anti-CD20, huIgG1 (Expressed on 90% B Cell Lymphomas) Rituximab™ </li></ul></ul><ul><ul><li>Anti-KSA (17-1A) Approved in Europe for Colorectal Cancer </li></ul></ul><ul><ul><li>Anti-Her 2/neu – huMAb, Overexpressed in 30% of Breast Cancers, Herceptin™ </li></ul></ul><ul><ul><li>BEC2 - Anti-Idiotypic Antibody </li></ul></ul><ul><ul><li>SEREX – Use of Serum From Responding Patients to Target Humoral Epitopes </li></ul></ul><ul><ul><li>Bispecific Antibodies – Antigens and Receptors on Effector Cells </li></ul></ul>
  37. 38. The Lore Out There <ul><li>Isotype of humoral response is important </li></ul><ul><ul><li>e.g. Clear Survival Advantage of IgM vs IgG Dominance – Has This Really Been Established? </li></ul></ul><ul><li>Th1 is More Important Than Th2 Response </li></ul>
  38. 39. Anything New? <ul><li>Vaccines Targeting CD1 </li></ul><ul><li>CD40/CD40L, Upregulating, Co-Stimulatory And Adhesion Molecules, B7-1, B7-2, ICAM-1, LFA3 on Surface of APCs, Toll-Like Receptors, CpG, HSPs </li></ul><ul><li>Myeloid Derived Suppressor Cells </li></ul><ul><ul><li>CD14+ HLA-DR neg </li></ul></ul><ul><li>Preventive Vaccines Gardisil® </li></ul><ul><li>More Trials, More Cells, Greater Integration and Combination of Approaches </li></ul>