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Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms & Their Application to Clinical Trials of Vaccines Part 2: the Vaccines Barbara K

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Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms & Their Application to Clinical Trials of Vaccines Part 2: the Vaccines Barbara K Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms & Their Application to Clinical Trials of Vaccines Part 2: The Vaccines Barbara K. Dunn NCI/Division of Cancer Prevention August 3, 2020 Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms and Therapeutic Approaches that are Relevant to Cancer Prevention I. Basic immunologic mechanisms II. Application to prevention & treatment of cancer 1. Antibodies: as drugs 2. Vaccines: general principles & your vaccine trials & more… I) Vaccines to prevent cancers caused by infectious agents II) Vaccines to prevent non-infection associated cancer (directed toward tumor associated antigens) Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms and Therapeutic Approaches that are Relevant to Cancer Prevention I. Basic immunologic mechanisms II. Application to prevention & treatment of cancer 1. Antibodies: as drugs “passive immunity” 2. Vaccines: general principles & your vaccine trials & more… I) Vaccines to prevent cancers caused by infectious agents “active II) Vaccines to prevent immunity” non-infection associated cancer (directed toward tumor associated antigens) Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms and Therapeutic Approaches that are Relevant to Cancer Prevention I. Basic immunologic mechanisms II. Application to prevention & treatment of cancer 1. Antibodies:Focus as on drugs the Antigen “passive !immunity” 2. Vaccines: general principles & your vaccine trials & more… I) Vaccines to prevent cancers caused by infectious agents “active II) Vaccines to prevent immunity” non-infection associated cancer (directed toward tumor associated antigens) DCP CONSORTIUM VACCINE TRIALS MAY2013-01-01 MUC 1/COLON Non-infection associated cancer MAY2013-02-01 VACCINE/HCV LIVER Infection associated cancer MAY2016-08-01 MUC-1/LUNG Non-infection associated cancer MDA2014-04-02 VADIS/BREAST Non-infection associated cancer Infection associated NWU2015-06-02 HPV 9-VALENT/TRANSPLANT cancer UAZ2014-03-01 PROSTVAC/PROSTATE Non-infection associated cancer Infection associated UAZ2015-05-01 HPV-9-VALENT/PEDIATRICS cancer UWI2014-03-01 WOKVAC/BREAST Non-infection associated cancer Vaccines - “active immunity” Adaptive Immune System KEY COMPONENTS OF VACCINES Antigen comes from the specific component: the nonspecific component: the thing you want to destroy: cancer cell, pathogen the Antigen the Adjuvant Peptide- long vs short Epitope (antigenicGenetic determinant vaccines:) = the partprotein of an antigen that is•DNA recognized (encodes by athe protein) immune system (antibodies,•RNA B vaccines cells, T cells); main Viralimmunogenic-like part of the vaccine Protein/ VLP Pentamer of a protein •Viral vector Adjuvants = agents added to vaccine formulations that Cell-based enhance the immunogenicity vaccines of antigens in vivo Vaccines - “active immunity” Adaptive Immune System KEY COMPONENTS OF VACCINES the specific component: the nonspecific component: the Antigen/Epitope the,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,,, Adjuvant Peptide- long vs short Platform technology Genetic vaccines: protein •DNA (encodes a protein) •RNA vaccines Viral-like Protein/ VLP platform Pentamer of a protein •Viral vector Adjuvants = agents added to vaccine formulations that Cell-based enhance the immunogenicity vaccines of antigens in vivo Vaccines - “active immunity” Adaptive Immune System KEY COMPONENTS OF VACCINES Antigen comes from the specific component: the nonspecific component: the thing you want to destroy: cancer cell, pathogen the Antigen the Adjuvant Peptide- Antigenlong vs short Genetic vaccines: protein •DNA (encodes a protein) •RNA vaccines Viral-like Protein/ VLP Platform Pentamer of a protein 1)Safety •Viral vector 2)Reactogenicity Adjuvants3)Immunogenicity= agents added: Endpoints:to vaccine formulations-seroconversion:Ab that Cell-based enhance the-neutralization:Ab immunogenicity vaccines of antigens- CD4,in vivo CD8 Tcell Vaccines - “active immunity” Adaptive Immune System KEY COMPONENTS OF VACCINES the specific component: the nonspecific component: the Antigen the Adjuvant Peptide- long vs short Epitope (antigenicGenetic determinant) vaccines: = the Adjuvant non- partprotein of an antigen that is•DNA recognized (encodes by athe protein) immune system (antibodies,•RNA B vaccines cells, T cells)specific stimulation to TargetsViral-like a specific Protein/ immune system = VLP antigen INNATE Pentamer= ADAPTIVEof a protein •Viral vector Adjuvants = agents added How do we pick the ■ Nonto vaccine-specific formulations Immuno- that Cell-based Modulatorsenhance the = INNATE immunogenicityonly antigen/epitope tovaccines target? of antigens in vivo Harnessing the Immune System to Prevent Cancer: Basic Immunologic Mechanisms and Therapeutic Approaches that are Relevant to Cancer Prevention I. Overview: Context of immunologic mechanisms: Elicitscarcinogenesis a specific response from the body’s own immune system: II. Structure/physicalFocus components on the Antigen and ! hierarchy of the immune system I. How immunologic mechanisms are used in medical interventions to treat and prevent cancer 1. Antibodies as drugs “passive immunity” 2. Vaccines: general principles & your vaccine trials I) Vaccines to prevent cancers caused by infectious agents “active II) Vaccines to prevent non-infection immunity” associated cancer (directed toward tumor associated antigens) Vaccines to prevent cancers caused by infectious agents Targets a specific How do we pick antigen the = ADAPTIVE antigen/epitope to target? The infectious agent is FOREIGN/NON-SELF →pick the antigen from this! JH February 13, 2018 HBV Vaccine HCV Vaccine example of antigen(s) derived from infectious agents, HBV, HCV Vaccines to prevent cancers caused by infectious agents Pathogenesis of Hepatitis B Virus-Associated Cancer Infects 350-400 million people (5% world population) Chronic HBV Carriers - incidence of HCC (hepatocellular carcinoma) ranges from 70% to 90% and nearly 100% in children Chronic HBV infection and high HBV DNA levels are a strong predictor for cirrhosis and HCC (irrespective of other viral and biochemical factors) Viral Viral Chronic Precancer Liver exposure infection Viral conditions Cancer infection Prophylactic vaccine Focus on the Antigen! HBV Vaccines (hepatitis B virus) HBV vaccine – FIRST vaccine in How do we pick the humans for cancer prevention (1981) antigen/epitope to target? -the Antigen: hepatitis B surface antigen The infectious agent is FOREIGN/NON- (HBsAg) = a viral envelope protein SELF →pick the antigen from this! • Pre-exposure prophylaxis/prophylactic vaccine • Vaccination with hepatitis B surface antigen (HBsAg) = a viral envelope protein – made from recombinant DNA, produced in yeast • Recombivax HB (Merck), Engerix-B (GSK), Elovac B (Human Biologicals Institute, Genevac B (Serum Institute), Shanvac B, etc. DCP CONSORTIUM VACCINE MAY2013-02-01 Therapeutic HCV vaccine Infection associated cancer chronic HCV infection example of antigen(s) derived from infectious agent, HCV no preventive vaccine for HCV Vaccines to prevent cancers caused by infectious agents Pathogenesis of Virus-Associated Cancer *Therapeutic from an infectious disease standpoint; actually prophylactic from a cancer standpoint Vaccines Viral Viral Chronic Precancer Cancer exposure infection Viral conditions infection Prophylactic Therapeutic vaccine vaccine DCP CONSORTIUM VACCINE Phase I Trial of a therapeutic DNA Vaccine for MAY2013-02-01 Chronic Hepatitis C Virus (HCV) Infection No therapeutic vaccine for HCV and HBV WHY VACCINE FAILURE? IMPAIRED T CELL RESPONSES CHRONIC HCV INFECTIONS immunoediting 96. - 54:1286 J. Hepatology 2011, Hepatology J. immunoediting T-Cell Exhaustion MAY2013-02-01 Therapeutic HCV vaccine Infection associated cancer antigen NS3 NS4B DNA plasmid vaccine NS5a platform chronic genotype 1 HCV infection w/plasma HCV RNA>10,000 IU/ml ↓ HCV genotype 1a/1b consensus DNA vaccine: encoding HCV NS3, NS4A; NS4B, NS5A Day 0; Weeks 4, 12, 24 ↓ 1o Endpoint: safety, AEs; immunogenicity: change HCV-specific IFN-Ɣ (wk 26) Translational Endpoints: virologic response (decrease in HCV RNA level) HPV Vaccines example of antigen(s) derived from infectious agent, HPV HPV Vaccines human papilloma virus - >100 strains: Some cause cancer -14 high risk Some cause warts Causes: ~100% of cervical cancers + head and neck cancers anal cancers L1 differs among strains Vaccines to prevent cancers caused by infectious agents VLP (L1s) HPV VACCINES (HUMAN PAPILLOMAVIRUS) How do we pick the Prophylactic (3 FDA Approved HPV vaccines) antigen/epitope to target? The infectious agent is -the Antigen: virus-like particles (VLP) from FOREIGN/NON-SELF →pick the antigen from major capsid proteins L1 = strain specific this! ●Bivalent/Quadrivalent subunit vaccines (HPV 16 and 18 – 70% of cervical cancers) Cervarix® (GSK-bivalent) (HPV 6 and 11 – majority of genital warts) Gardasil ® (Merck-quadrivalent) Vaccines 98% effective preventing high-grade cervical lesions Approved: ● Nonavalent vaccine (V503, Merck) (FDA approval Dec 2014) females 9-26 HPV 6/11/16/18/31/33/45/52/58–Gardasil 9® males 9-15 ●Bivalent (HPV 16 and 18)(Xiamen Innovax Biotech Co) John Schiller’s lectures-July 2018 (China: approved Jan 2,2020) - Cecolin July 21,2020 Vaccines to prevent cancers caused by infectious agents Pathogenesis of HPV-Associated Cancer & Vaccines to Prevent Cervical Cancer Cervical Viral Viral Chronic Precancer Cancer exposure infection Viral conditions infection
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