Immunotherapy Notes

Describe different types of immunotherapy:
- Active Immunisation
- Passive Immunisation
- Antibody-based Immunotherapy
- Immune Modulation
- Cell-based Therapies
- Stem Cell Transplantation
- Gene Therapy
Review the advantages and disadvantages of inactivated vaccines compared with live attenuated vaccines.

Provide antibodies (immunoglobulin, Ig).
Allows immediate protection, but no immune memory is developed.
Examples:
- Maternal antibodies transferred in colostrum.
- Normal Ig from pooled plasma.
- Specific Ig from source of high titre antibodies to a specific organism/protein.
Indications:
- Exposure has occurred recently or is expected soon.
- No effective vaccine, or time too short, or vaccine is contraindicated for this patient.
Standard Ig:
- Immunodeficiency or immunocompromised states, as it provides broad protection against common pathogens.
Specific Ig:
- Anti-venom:
  - Venom milked from snake, spider, etc.
  - Injected in diluted form into animal species.
  - Hyperimmune Ig isolated for post-bite therapy.
- Convalescent serum:
  - Purified from individuals post infection (e.g., CMV, Herpes).

Mimic natural infection by replicating in the recipient after administration.
Often, both antibodies and immune memory are triggered, leading to long-term or even life-long protection.
Adjuvant is not required.
Fewer doses may be required.

May get a weakened disease pattern in a small proportion of recipients (e.g., fever and occasional rash after measles vaccination).
May retain some pathogenicity (theoretical potential to revert to wild virus).
May not be safe enough for pregnant or immunocompromised patients.
Requires a suitable ‘cold chain.’

Diphtheria-Tetanus-Pertussis-Polio: 2, 4, 6 months and 4 years
Haemophilus influenzae type B: 2, 4, 6 and 18 months
Hepatitis B: Birth, 2, 4 and 6 months
Pneumococcal: 2, 4, 12 months
Rotavirus: 2, 4 months (*Live attenuated vaccine)
Meningococcal ACWY: 12 months
Measles-Mumps-Rubella: 12 and 18 months (*Live attenuated vaccine)
Varicella (given in combination with MMR): 18 months (*Live attenuated vaccine)

Monoclonal antibodies provide the possibility to target a specific molecule, giving great therapeutic potential.
Can also be ‘humanised’ to provide increased tolerability.
Provide for antibody-mediated cell killing or can be linked with other molecules, including cytotoxics.
Examples:
- Anti-CD20 (rituximab): Targets B cells; Used in Non-Hodgkin Lymphoma.
- Anti-IgE (omalizumab): Targets excess IgE; Used in allergy/anaphylaxis.

Cytokines: A range of cytokines are able to modulate immune cells and their responses:
- G-CSF: Neutrophil restoration
- IL-7: Lymphoid cell restoration
- IL-12: Immune enhancement
- Interferons: Anti-cancer/anti-infective
- TNFα: Anti-cancer
Immunosuppression: In certain clinical conditions, it is advantageous to suppress the immune system:
- Autoimmune disease
- Organ transplantation
- Examples:
  - Glucocorticoids: Anti-inflammatory
  - Methotrexate: Broad anti-immune
  - Cyclosporin: Anti-T cell

Can also utilise a patient’s own immune cells to assist in therapy (especially anti-cancer) – ‘Adoptive Immunotherapy’
Examples:
- Dendritic cell-based: Patient DCs extracted and pulsed with antigen, before returning to patient.
- T-cell adoptive transfer: Patient tumour-infiltrating lymphocytes (TILs) extracted and expanded with IL-2 before returning to patient.

In a number of cases, the replacement of a patient’s immuno-haematological cells is a favorable option:
- Cancers and proliferative disorders of blood and immune cells
- Immunodeficiencies
Major sources of these stem cells:
- Bone marrow
- Peripheral blood (following mobilisation with G-CSF, etc.)
- Cord blood
Stem cells used are either:
- Autologous (from the patient)
- Allogenic (from a ‘matched’ donor)
Stem cell transplantation requires ‘conditioning’ – ablation of bone marrow with toxic chemicals.
Allogenic transplantation may require immunosuppression but can also provide anti-tumour activity (‘graft versus tumour’).

Definition: The delivery of genetic material to cells in order to alter genes or gene expression for therapeutic reasons.
Several different approaches to:
- Increase expression of a therapeutic gene
- Inhibit the expression of a disease gene
- Correct a genetic defect
Two major methods of delivery:
- In vivo: Direct transfer of genetic material to cells in the body.
- Ex vivo: Removal of patient cells, gene delivery in culture, and then return of cells to the patient.
Gene Inhibition: Useful approach for blood and immune cancer
- Inhibit expression at the DNA level, the RNA level, or the protein level (e.g., oncogene):
  - Triplex-forming oligonucleotides (TPO): form complex with DNA
  - Antisense oligonucleotides: bind to mRNA
  - Ribozymes: has enzymatic ability to cleave RNA
  - Antibodies/aptamers: target proteins
Gene Replacement: The ultimate treatment for many immunological diseases is to permanently correct a gene defect in order to restore health
- Example: Severe combined immunodeficiency (SCID) caused by adenosine deaminase (ADA) deficiency
  - ADA-SCID patients suffer from:
    - a lack of T cells
    - recurrent, life-threatening infections
  - Introduction of a functional ADA gene can overcome the defect