Therapeutic Vaccines

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Therapeutic Vaccines
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Behavioral objectives

• List 5 conditions or diseases that therapeutic
  vaccines might alleviate
• Discuss 3 strategies that can be used to develop
  an anticancer vaccine.
• List 5 mechanisms that protect tumor cells from
  destruction.
• Just know it all.

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Therapeutic Vaccines Aimed at Noninfectious
Problems

• Cancer
• Alzheimers disease
• Autoimmune diseases
• Allergic diseases
• Obesity
• Drug addiction
• Smoking

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AIM of Cancer Vaccines

• Therapeutic vaccines
• To induce tumor- antigen specific responses in
  patients that will destroy primary tumors and/or
  metastatic tumors or prevent further tumor
  growth.
• Prophylactic vaccines
• Injected into healthy people to prevent
  development of cancer
• Anti-oncogenic viral vaccines (anti-HPV
  anti-hepatitis B).

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Targets for Immunization

• Cancer antigens are proteins or carbohydrates
  that stimulate immune responses.
• Normal nonmutated differentiation antigens
  excessively expressed on specific tumor cells
  (melanomas).
• Cancer antigens widely expressed on a
• variety of epithelial tumors as well as on
  testes and placental tissue.
• Normal proteins that contain mutations or
  translocations that give rise to unique epitopes.
• Nonmutated shared antigens that are over
  expressed on cancer cells(Her-2/neu, p53,
  carcinoembryonic antigen).

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Immunization approach

• Target receptors for tumor growth or surface
  antigens.
• Target tumor specific antigenic epitopes
  presented in MHC class I molecules to T cells.

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Strategies

• Identify a unique or unusual cancer cell antigen
  not found on normal cells.
• Identify antigens that are found on normal cells
  but are over-expressed on cancer cells.
• Alter aa structure of cancer antigen to make it
  more immunogenic.
• Place cancer antigen gene into a viral vector.
• Add immunostimulatory molecule genes plus cancer
  antigen gene to a viral vector.
• Conjugate cancer epitopes with adjuvants.

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Encouraging Results for the Development of
Anti-cancer Vaccines

• Spontaneous regression of some tumors.
• Autologous T cells from cancer patients recognize
  tumor-specific antigens.
• Antigens encoded by genes of MAGE family have
  been identified as tumor-specific MAGE peptides.
  Immunization of patients with metastatic melanoma
  with MAGE 3 peptides reduced tumor size in a
  significant number of patients and generated a
  cytotoxic T cell response in one patient.
• Heat shock proteins that bind small antigenic
  peptides can suppress tumor growth.

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Why is it difficult to make efficacious
anti-cancer vaccines

• Immune system fails to recognize cancer cells
  or responds poorly to their presence

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Mechanisms by Which Cancer Cells Escape or Avoid
Immune Destruction

• Antigen-specific T cells too few or lack efficacy
  against tumor cells.
• Lack of co-stimulation molecules on tumor cells
  or down-regulation of T cell receptor signal
  transduction.
• Down-regulation of MHC expression on tumor cells.
• Immunosuppression by factors released from tumor
  cells.

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Therapeutic cancer vaccines under investigation

• Antigen/adjuvant vaccines
• Whole cell tumor vaccines
• Dendritic cell vaccines
• Viral vector and DNA vaccines
• Idiotype vaccines

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Cancer Vaccines Phase III Trials

• Follicular B-cell Non-Hodgkins lymphoma.
• Kidney cancer
• Cutaneous Melanoma
• Prostate cancer
• Multiple Myeloma

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Vaccines for Alzheimers Disease

• A dementia characterized by progressive mental
  deterioration.
• 12,000,000 estimated to be afflicted in USA and
  EU countries.
• Neuropathological hallmarks include extracellular
  deposits of senile amyloid plaques,
  intra-neuronal neurofibrillary tangles, synapse
  loss, death of neurons.

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Vaccine target

• Plaques containing ?-amyloid, a 39-43 aa peptide
  produced by normal cells cleaving the ?-amyloid
  precursor protein (APP).
• 2 cleavage pathways one yields a 40 aa peptide
  (A????? which is more soluble and aggregates
  slowly, the second is a 42 aa peptide (A?-42)
  which is insoluble and forms ?-pleated sheets

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Progress to Date

• Antibodies to A?????can induce clearance of
  plaques in mice, similarly a vaccine can reduce
  deposition of amyloid into existing plaques and
  partially cleared senile plaques.
• Clinical studies in humans resulted in side
  effects, brain inflammation in some patients.
• ? transcutaneous ??amyloid?vaccine in mice did
  not produce side effects.

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Immunological Approaches to the Therapy of
Autoimmune Diseases

• Global immunosuppression.
• Altering T cell receptor signalling.
• Costimulatory blockade.
• Soluble mediator-directed immunomodulation.
• Vaccines

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Therapeutic Vaccines for Autoimmune Diseases

• Aim to induce T cell tolerance.
• T cell vaccination.
• T cell receptor/peptide vaccination.
• DNA vaccination.
• Vaccination with altered peptide ligand.

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Autoimmune Diseases

• Comprise more than 70 clinically distinct
  diseases.
• gt30,000,000 people in USA EU countries
  afflicted.
• Some autoimmune diseases increasing in
  prevalence.
• Social and financial burden immense.

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• Rituximab anti-CD20(B cells) mAb.
• hOKT3y (ant-CD3 mAb).
• Worm therapy for MS (induceTh2 response).

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TherapeuticVaccines for Allergic Diseases

• Allergic diseases affect gt30 of the population
  in some countries. 7 have asthma in US alone
  and 20 suffer from allergic rhinitis.
• Allergy associated health costs gt14 billion in
  2000.

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Reasons to Explain the Trend in the Prevalence of
Allergic Diseases

• Hygiene Hypothesis-declining incidence of many
  infectious diseases and delayed infant
  colonization with commensal microorganisms favors
  an increase in Th2 bias of immune responses
  toward environmental allergens.

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Approach

• Protein-based immunotherapy-desensitization-best
  for insect venoms but less so for rhinitis and
  asthma.
• More recently clinically important allegens have
  been identified, purified, cloned and epitope
  mapped.
• Combined with non-antigen specific methods show
  promise as therapeutic vaccines.

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Vaccines for Addiction

• Anti-smoking vaccines
• Anti-narcotic vaccines
• Anti-obesity vaccines

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• Most are aimed at inducing antibodies that bind
  active drug components in blood and prevent
  passage through he blood-brain barrier to reach
  receptors triggering pleasure and behavioral
  effects.
• Anti-obesity vaccines aimed at reducing blood
  levels of ghrellin

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Anti-Drug Vaccines
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• Ghrelin, a gastric endocrine hormone produced
  primarily in the stomach, plays a physiological
  role in energy homeostasis. It is a naturally
  occurring ligand-a molecule that binds to another
  to form a larger molecular complex-for a growth
  hormone secretagogue receptor. Ghrelin promotes
  weight gain and fat storage through its metabolic
  actions, decreasing the breakdown of stored fat
  for energy as well as curbing energy expenditure
  itself. During periods of weight loss, such as
  dieting, the body produces high levels of ghrelin
  to slow down fat metabolism, encourage eating,
  and promote fat retention, changes which normally
  make it difficult to lose weight and keep it off.