Immunotherapy
Introduction
The aim of this chapter is to give an overview of the very complex but exciting area of immunotherapy. Despite great advances in the basic science, the results of clinical immunotherapy have not been as good as had been hoped. Nonetheless, the advances in basic immunology continue to provide new avenues to explore.
Major mechanisms of immunomodulation
Immunization:
active
passive.
Replacement therapy:
C1-esterase inhibitor
α1-antitrypsin
plasma.
Immune stimulants:
drugs
cytokines.
Immune suppressants:
drugs
monoclonal antibodies
cytokines and antagonists
antibody removal (plasmapheresis).
Desensitization:
bees and wasps
other allergens.
Anti-inflammatory agents:
anti-cytokines (anti-TNF) IL-1ra
anti-complement mAbs
anti-endotoxin mAb
anti-T cell/anti-B cell mAbs.
Adoptive immunotherapy:
bone marrow transplantation
stem cell transplantation
?thymic transplants.
Passive immunization
Protection is provided by transfer of specific high-titre antibody from donor to recipient. The effect is transient (maximum protection 6 months). Protection is immediate (unlike active immunization).
Problems
Risk of transmission of viruses.
Serum sickness (including demyelination), acute reactions.
Development of antibodies against infused antibodies reduces effectiveness.
Identification of suitable donors (Lassa fever, rabies).
Types
Pooled specific human immunoglobulin.
Animal sera (antitoxins, antivenins).
?Monoclonal antibodies (anti-endotoxin).
Uses
Hepatitis A prophylaxis (but new vaccine provides active immunization and longer prophylaxis).
Hepatitis B (for needlestick injuries), tetanus, rabies, Lassa fever.
Botulism, VZV (especially during pregnancy and in the immunocompromised), diphtheria, snake bites (post-exposure).
Rhesus incompatibility (post-delivery anti-D).
Active immunization
The purposes of active immunization are as follows.
To stimulate the production of protective antibody (opsonization, complement fixation, enhanced phagocytosis, blocking uptake (virus neutralization)).
To stimulate antigen-specific T cells: whether these are Th1 or Th2 cells depends on the type of pathogen and the optimal protective response.
To produce long-lasting immunological memory (T and B cells).
Mediated by the retention of antigen on follicular dendritic cells in lymph nodes, leading to a long-term depot.
Hence antibody levels often persist years after the primary course of immunizations has been completed, rather than decaying to zero.
To produce ‘herd immunity’: the generation of a sufficiently large pool of immune individuals reduces the opportunity for wild-type disease to spread, increasing the effectiveness of the immunization programme:
immunization rates>75% are required to achieve this.
Active immunization can use:
purified component, e.g. toxin (inactivated = toxoid)
subcomponent
live attenuated pathogen (e.g. BCG, polio).
Active immunizationcan be combined with passive immunization (although this may reduce the development of long-term immunological memory).
This approach is used for tetanus and rabies as a strategy for treatment post-exposure.
Toxoid/subcomponent vaccines
Immune response frequently requires augmentation with adjuvants.
May be side effects from adjuvants.
No risk that disease will be produced.
Inactivation may damage key epitopes and reduce protection.
Safe to use in the immunocompromised but responses (and protection) unpredictable.
Attenuated vaccines
Usually more immunogenic and do not require adjuvants.
Risk of reversion to wild type (e.g. polio).
Side effects from culture contaminants (demyelination from duck embryo rabies).
May produce mild form of disease (measles, mumps).
Contraindicated in immunosuppressed (paralytic polio in antibody deficiency).
Unexpected viral contaminants (SV40, polio; hepatitis B, yellow fever).
General problems of active immunization
Active immunization has a number of problems, including the following.
Allergy to any component (e.g. residual egg protein, often in viral vaccines from the growth media).
Reduced/absent responses in immunocompromised (including splenectomy).
Delay in achieving protection (primary and secondary immune responses require multiple injection schedules).
route of administration may determine the type of immune response
route to be relevant for the route of infection of the pathogen (e.g. need for mucosal immunity to enteric organisms).
Storage: most live vaccines require refrigerated storage to maintain potency; this may be a problem, especially in tropical countries.
Age at which a vaccine is administered may alter the response, e.g. responses to polysaccharide antigens are poor in:
children under the age of 24 months
the elderly.
Maternal antibody, passive immunization, concomitant medical illness, and associated drug therapy may reduce the response.
Ideally, responses should be checked serologically in patients where there may be a poor response.
Serological unresponsiveness does not preclude good T-cell immunity (hepatitis B).
Anti-self-immune response to immunization (e.g. autoimmunity after meningococcus group B polysaccharide administration).
Multiple immunogenic strains of target organism (e.g. Meningococcus, Pneumococcus).
Additional stimulation of the immune system
Poorly immunogenic antigens can be used if combined with agents that non-specifically increase immune responses (‘adjuvants’). Adjuvants mimic PAMPs (pathogen association molecular patterns), increase the innate immune response via TLR, and augment the activity of dendritic cells macrophages and lymphocytes.
Adjuvants.
‘Depot’ of antigen (alum-precipitated; oil), squalene
Non-specific stimulation (Freund’s adjuvant, MDP). Freund’s adjuvant is too potent to be used in humans! However, it has been safely used in microlitre quantities.
Polymerization (liposomes, ISCOMs—Quil A).
unmethylated CpG dinucleotides.
expression in vectors (e.g. use of vaccinia, chimeric viruses, BCG, Salmonella).
Virosomes (membrane-bound haemagglutinin and neuraminidase from influenza virus)—facilitates uptake into antigen-presenting cells.
Use of immunogenic carrier proteins conjugated to primary antigen:
tetanus toxoid
diphtheria toxoid.
Modern approaches to vaccine development
Development of more potent but safer vaccines is always the goal.
Molecular techniques have been used to modify pathogens by sitespecific mutation, reducing pathogenicity, or inserting the gene into a carrier (vaccinia, Salmonella).
Development of the host response to the carrier organisms means that it can only be used once.
Molecular techniques allow the safe synthesis of bulk quantities of antigen (e.g. hepatitis B surface antigen).
Recombinant technique needs to be selected carefully to ensure appropriate post-translational glycosylation of the antigen.
Recombinant organisms can also be used to target antigens to particular cells. For example:
Salmonella is rapidly taken up by macrophages
inserted gene products will also be directed straight to antigen-presenting cells.
Conjugation of poorly immunogenic antigens (such as polysaccharides) to immunogenic proteins (tetanus, diphtheria toxoids).
Humoral immune response to the polysaccharide switches from IgG2 to IgG1 and IgG3.
Specific peptides are being used experimentally to try to stimulate specific T-cell responses.
Epitope mapping of antigens to determine the T- and B-cell epitopes is required.
Direct injection into muscle of nucleic acid (RNA, DNA) coding for specific genes, coupled to gold microsphere carriers or in plasmids, generates an immune response.
Nucleic acid is not degraded but is taken up into myocytes and specific protein production can be detected for several months thereafter, leading to an excellent depot preparation.
Concern over risk of bystander attack by the immune system on myocytes containing the injected DNA.
Generation of effective response
To generate an effective immune response, both host and pathogen factors need to be taken into account. Factors encouraging the development of an effective vaccine involve both infectious agent factors and host factors.
Infectious agent factors.
One or a small number of serotypes; little or no antigenic drift.
Pathogen is only moderately or poorly infectious.
Antigens for B- and T-cell epitopes are readily available.
The immune response can be induced readily at the site of natural
infection.
Wild-type infection is known to produce protective immunity.
Availability of animal models to test vaccine strategies.
Host factors.
Humoral and cellular immunity is readily induced.
MHC background of population is favourable to a high response.
Factors in the infectious agent that mitigate against an appropriate immunization response and therefore prevent the development of good vaccines include the following.
Marked antigenic variation/drift; many serotypes causing disease. This limits the ability to generate an effective vaccine (e.g. pneumococcal disease).
Potential for change in host range of the pathogen (e.g. change in cell tropism of viruses such as HIV).
Infection may be transmitted by infected cells that are not recognized by the immune system even after immunization.
Integration of viral DNA into the host genome (latency).
Natural infection does not induce protective immunity.
Pathogen uses ‘escape’ mechanisms:
resistant external coats (e.g. mycobacteria)
poorly immunogenic capsular polysaccharides
antigenic variation in response to host immune recognition (e.g.
influenza virus, malaria)
camouflage with host proteins (e.g. CMV and β2-microglobulin)
production of proteins similar to host proteins (e.g. enterobacteria) may give rise to autoimmunity
extracellular enzyme production to interfere with host defence (staphylococcal protein A)
production of molecules that disrupt immune responses (e.g. superantigens).
Pathogen-induced immunosuppression (HIV).
Failure to form appropriate response (e.g. complement-fixing antibodies).
No suitable animal model.
Host factors that mitigate against an appropriate immunization response and therefore prevent the development of good vaccines include the following.
Immune response is inappropriate, e.g. antibody when cellular response is required (e.g. leishmaniasis).
Immune response enhances infection, e.g. antibody formation may enhance infection through increased uptake into macrophages (yellow fever, ?HIV).
Cells of immune system are target of infection.
‘Wrong’ MHC background predisposes to low response or autoimmunity.
The ultimate goal of any immunization programme is the eradication of the disease. This requires that:
the infection is limited only to humans
there is no animal or environmental reservoir
absence of any subclinical or carrier state in humans
a high level of herd immunity can be established to prevent person-toperson spread:
this requires considerable infrastructural support to ensure that all at-risk populations are targeted for immunization
this has only been achieved for smallpox
however, herd immunity for smallpox has waned as immunization programmes have stopped; bioterrorism with smallpox is a significant threat.
‘Replacement’ therapy
This is used for treatment of primary and some secondary immune deficiencies (see Table 16.1).
Table 16.1 Replacement therapies for some primary and secondary immune deficiencies | ||||||||||||||||||||||||||||||
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Intravenous immunoglobulin (IVIg) for replacement therapy 1
Manufacture and specification
IVIg is a blood product prepared by cold ethanol precipitation of pooled plasma.
UK plasma is not currently used (risk of prion disease); no test currently available to identify prion disease in donors.
Donated plasma is usually quarantined until donor next donates (avoids undetected infection at time of first donation).
Donor pool usually >1000 donors to ensure broad spectrum of antibody specificities.
Subsequent purification steps vary between different manufacturers but all are based on the original Cohn fractionation process.
The IgA content is variable.
Significant levels of IgA may be important when treating IgA-deficient patients, who may recognize the infused IgA as foreign and respond to it, leading to anaphylactoid responses on subsequent exposure.
It is uncertain how much of a problem this is, and there is no standardized method for detecting clinically significant anti-IgA antibodies.
All current UK products have low/undetectable IgA.
Product must have low levels of pre-kallikrein activator, Ig fragments, and aggregates as these three can cause adverse events on infusion.
Variations of IgG subclasses do not seem to make significant differences to the effectiveness as replacement therapy.
Comparing the presence of functional antibodies in individual products is difficult as there are no internationally standardized assays, but IVIg must have intact opsonic and complement-fixing function.
All licensed products must have at least two validated antiviral steps:
cold ethanol precipitation
pH4/pepsin
solvent/detergent treatment
pasteurization
nanofiltration.
Model viruses are used to demonstrate that the process is effective
No product should be viewed as virally ‘safe’.
Full counselling about risks and benefits must be given to patient, with written information, and this must be recorded in the medical notes.
Written consent must be obtained prior to therapy and retained in the medical notes.
A pre-treatment serum sample should be stored, to facilitate ‘look-back’ exercises if required
Liquid preparations are now preferred for ease of administration.
Most manufacturers are moving to 10% solutions, with more rapid infusion times. 20% solutions of SCIg are now available; standard SCIg is 16%.
Uses
IVIg (or SCIg—see ‘Intramuscular and subcutaneous immunoglobins for replacement therapy’, p.396) is mandatory for replacement in:
combined immunodeficiencies (pre- and immediately post-BMT).
IVIg is also recommended in patients with secondary hypogammaglobulinaemia, such as CLL and myeloma, postchemotherapy etc. (see Chapter 2).
The role of IVIg in IgG subclass and specific antibody deficiency is less secure, and regular prophylactic antibiotics might be tried first, with IVIg reserved for continuing infection despite therapy (assess risk-benefit).
Where there is doubt, a 1-year trial is reasonable, with monitoring of clinical effectiveness through the use of symptom diaries.
To ensure a realistic trial, adequate dosing and frequency of infusions must be undertaken to ensure that benefit will be obvious.
Dose regime
Treatment should provide 0.2-0.6g/kg/month given every 2-3 weeks for primary antibody deficiency, or as an adjunct in combined immunodeficiency.
Older patients with CLL may manage on monthly infusions.
Most patients on monthly schedules become non-specifically unwell or develop breakthrough infections after 2-3 weeks.
Under these circumstances the interval should be shortened.
Rare hypercatabolic patients, or those with urinary or gastrointestinal loss, may require weekly infusions of large doses to maintain levels.
Adjust dose according to the trough IgG level, aiming to achieve a trough IgG level within the normal range (6-16g/L).
Aim for higher trough in patients with established bronchiectasis or chronic sinusitis (target trough 9g/L), as this will reduce lung damage.
Breakthrough infections are an indication to reassess interval and target trough level.
IVIg for replacement therapy 2: adverse reactions and risks of infection
Adverse reactions
Most adverse reactions are determined by the speed of infusion and the presence of underlying infection.
Untreated patients receiving their first infusions are at most risk.
Reactions are typical immune complex reactions:
headache
myalgia
arthralgia
fever
bronchospasm
hypotension
collapse
chest pain.
Pre-treatment of the patient with antibiotics for 1 week prior to the first infusion reduces antigenic load and reaction risk.
Hydrocortisone (100-200mg IV) and an oral antihistamine (cetirizine, fexofenadine) given before the infusion are also of benefit.
The first infusion should be given at no more than two-thirds of the manufacturer’s recommended rate.
Start slowly and increase rate in steps every 15 minutes.
Similar precautions may be required before the second infusion.
Reactions may occur in established recipients if:
there is intercurrent infection
there is a batch or product change.
Other adverse events include:
urticaria
eczematous reactions
delayed headache and fatigue (responds to antihistamines!)
medical problems from transferred antibodies (e.g. ANCA—uveitis).
Aseptic meningitis—usually seen with hdIVIg, but occasionally with replacement doses.
Products should only be changed for clinical not financial reasons.
Severe anaphylactoid reactions have been reported after switching products.
IVIg products are not interchangeable.
Risk of infection
Infection remains a major concern:
hepatitis B is no longer an issue
there have been a significant number of outbreaks of hepatitis C
other hepatitis viruses (HGV) may cause problems
no risk of HIV transmission, as the process rapidly destroys the virus
safety in respect of prion disease is not known, but risk will be cumulative with continuing exposure
Antiviral steps reduce but do not eliminate risk.
Batch exposure needs to be kept to a minimum.
Batch records must be kept to facilitate tracing recipients.
IVIg for replacement therapy 3: monitoring and home therapy
Monitoring
Store pre-treatment serum long-term.
Monitor trough IgG levels on all patients regularly (alternate infusions).
Monitor liver function (alternate infusions, minimum every 3-4 months)—transmissible hepatitis.
Monitor CRP—evidence of infection control.
Record batch numbers of all IVIg administered.
Use symptom diaries in appropriate patients to monitor infective symptoms, antibiotic use, and time off work/school.
In the event of a significant adverse reaction:
immediate blood sampling for evidence of elevated mast-cell tryptase, complement activation (C3, C4)
send sample for anti-IgA antibodies (if IgA deficient)
screen for infection (CRP, cultures).
Rare antibody-deficient patients seem to react persistently to IVIgs; changing to a different product may sometimes assist. Occasionally continued prophylactic antihistamines, paracetamol, or even steroids may be required before each infusion to ensure compliance with therapy.
Home therapy
For patients with primary immunodeficiencies, home treatment is a well-established alternative to hospital therapy.
Criteria for entry to home therapy programmes are laid down in approved guidelines (see Table 16.2).
Specific centres in the UK are recognized as being able to provide appropriate training.
Patients should not be sent home on IVIg without formal training and certification by an approved centre.
The centres will also arrange for long-term support, with trained home therapy nurses and support from community pharmacy suppliers.
UK Primary Immunodeficiency Network (www.ukpin.org.uk) can provide details of approved centres in the UK. The International Patient Organization for Primary Immunodeficiencies (IPOPI) can provide details of overseas contacts.
Home therapy is not available in all countries for legal and/or financial reasons.
Table 16.2 Criteria for home therapy | ||||||||||||||||||||
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Intramuscular and subcutaneous immunoglobulins for replacement therapy
Intramuscular immunoglobulin (IMIg)
There is no role for IMIg in replacement therapy. Administered doses are too low to be effective in preventing infection. However, occasional older patients prefer the convenience of a weekly injection at their GP‘s surgery to hospital-based infusions. IMIg has been associated with an adverse reaction rate of 20%.
Subcutaneous immunoglobulin (SCIg)
For those with poor venous access, high-dose SCIg replacement is at least equivalent to IVIg in terms of maintaining adequate trough IgG levels and preventing infection.
16% solution of immunoglobulin is used; 20% solution now also available.
Specific licensed SCIg preparations are now available from several manufacturers.
It is administered via a syringe driver in a weekly dose of 100mg/kg at multiple sites.
One or two infusion pumps may be used, depending on type and availability.
Rate is usually set to the maximum; some pumps use restrictors on the giving sets.
Usual maximum tolerated dose is 10mL per site; products with enzymes to aid dispersal are being developed and may allow larger doses to be given at single sites.
Tolerability is reasonable, with local irritation being the only significant side effect.
Home therapy can be undertaken (for guidance, see ‘IVIg for replacement therapy 3’, p.395).
Trough levels tend to run approximately 1g/L higher than the same dose given as IVIg on a 2-3-weekly cycle.
Syringe drivers must be checked at least annually by a qualified medical electronics technician.
C1-esterase inhibitor for replacement therapy
Deficiency of C1-esterase inhibitor causes episodic angioedema, which may be fatal if it involves the upper airway (see Chapter 1).
Purified C1 inhibitor is available in the UK as Berinert®, Cinryze®, and Ruconest®.
These are blood-derived products and carry the same risks as IVIg with respect to tranmissible infections.
Products undergo viral inactivation steps (steam treatment).
Patients should have samples checked for LFTs and HCV status prior to each course of treatment.
Appropriate consent should be obtained if possible.
Batch numbers must be recorded.
Indications for treatment include:
attacks above the shoulders
surgical prophylaxis (including major dental work).
Weekly administration has been used in pregnancy where there are frequent severe attacks.
It is less effective against bowel oedema, but if pain is severe one dose should be given.
Attacks involving the bowel should be treated with fluids, analgesics, and NSAIDs.
Surgery should be avoided unless there is good evidence for pathology unrelated to HAE.
Dose is 500-1500U (1-3 ampoules) administered as a slow bolus IV.
Manufacturer’s information and guidelines suggest that the higher dose is required, but this is not always true.
Levels of C1-esterase inhibitor level in the serum should rise to >50% for several days.
Same dose is used for prophylaxis.
When used as treatment, it will prevent attacks progressing, but will not lead to a dramatic resolution of symptoms. Accordingly, laryngeal oedema may require other measures, such as tracheostomy, as urgent procedures.
Recombinant C1-esterase inhibitor, produced in rabbit milk (Rhucin®), is now available; known allergy to rabbits precludes treatment because of a risk of anaphylaxis. Recipients must be screened annually for the development of anti-rabbit IgE antibodies. It has a short half-life compared with Berinert® and therefore is only suitable for acute treatment.
Purified-blood-derived nanofiltered C1 esterase inhibitor, Cinryze®, is also now licensed, As it is blood derived, unlike Rhucin®, normal precautions relating to the use of blood products should be observed, as for Berinert®.
Plasma can be used if the purified concentrate is unavailable, but is less effective and may even increase the oedema by providing fresh substrate for the complement and kinin cascades.
Pooled virally inactivated fresh frozen plasma is now available, and may carry a reduced risk of infection, although this is debated.
On the whole, plasma should be avoided unless there is no alternative in the emergency situation.
Other immunotherapies for hereditary angioedema (HAE)
Other therapies for the acute treatment of HAE, which avoid the use of blood-derived and recombinant C1 esterase inhibitor, are now available.
Icatibant (Firazyr®) is a bradykinin B2 receptor blocking drug, which is effective at reducing the symptoms of acute attacks of HAE.
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