healthmedicinet

Helminth therapy in humans

To date two species of helminths have been tested for human helminth therapy as a
clinical treatment, Trichuris suis, the pig whipworm, and the human hookworm Necator americanus. After ingestion of T.suis ova (TSO), the eggs hatch and the worms colonise the caecum and colon of the human
gut for only a short period of time (weeks) meaning that treatments need to be repeated
at intervals, however, this species-specificity and lack of chronic infection is beneficial
in the sense that it also removes any wider public health issues. Larvae of the human
hookworm Necator, however, are administered percutaneously and migrate through the vasculature and
lungs to the small intestine where they survive by feeding on blood from the mucosa,
giving rise to long lasting infections (years) and may at higher doses cause clinical
symptoms such as gastrointestinal symptoms and anemia. In its natural state this infection
is a major public health problem across the globe and large-scale deworming programs
are in place to combat the morbidity associated with natural infection 13].

Helminth therapy used to alleviate intestinal inflammation

Several studies in animal models have demonstrate that intestinal helminth infections
are able to inhibit the development of intestinal inflammation (reviewed in 14],15]) and the first clinical studies of helminth therapy in humans started some 10–15
years ago with the use of the pig whipworm Trichuris suis. In initial safety studies patients with Ulcerative colitis (UC) or Crohn’s disease
were given viable, embryonated T.suis eggs (TSO) and not only was the treatment well tolerated but a significant disease
remission was observed and although the beneficial effect was temporary, repeated
doses of TSO sustained this clinical improvement suggesting a promising new therapy
for IBD 16],17]. A placebo–controlled, double blind, randomised trial in Ulcerative colitis patents
followed, showing significantly improved disease activity index in TSO treated patients
compared to placebo, although the remission rate was no different between the two
groups 18]. Further development and safety testing of TSO under GMP was performed and a small
randomized double-blind placebo controlled study reported that Crohn’s patients receiving
a single dose of up to 7500 TSO did not show any short (2 weeks) or long term (6 months)
adverse effects 19] opening up the field towards larger clinical trials. To date at least six clinical
trials using TSO in Crohn’s or UC patients have been registered as recruiting, ongoing
or completed. However, in October 2013 Coronado biosciences announced in a press release
that the results from the first larger study (TRUST-1, trial identifier NCT01576471),
a Phase 2 clinical trial evaluating TSO in 250 US patients with moderate-to-severe
Crohn’s disease, did not meet its primary endpoint of improving responses, either
in terms of improving disease activity index or remission rates, although a non-significant
improvement was noted in patients with a more severe disease score 20]. Shortly after, a second Corona press release announced the discontinuation of the
Phase 2 study of 240 European Crohn’s patients (FALK, trial identifier NCT01279577)
after an independent monitoring committee recommended its discontinuation due to “lack
of efficacy” 21]. No further data has been released from either study. Although the clinical trial
results for TSO therapy in Crohn’s patients are disappointing, results from several
Ulcerative colitis trials are still eagerly awaited.

A second approach to helminth therapy has been the slightly more controversial use
of the human hookworm Necator, a pathogen responsible for much of the morbidity associated with intestinal helminth
infections around the globe. In a small trial where 9 Crohn’s patients were infected
with 25–50 larvae and followed over 20 weeks, 7 patients experienced improved disease
score while 2 experienced a worsening effect 22]. A second study examined hookworm versus placebo therapy in a cohort of 20 coeliac
disease (gluten allergy) patents followed by wheat challenge after 20 weeks. The dose
of 5–10 larvae was generally well tolerated and immunological analysis demonstrated
reduced inflammatory cytokine (IFN-? and IL-17) responses in duodenal biopsies from
hookworm compared to placebo-treated patients 23], however there was no difference in the symptomatic response to wheat challenge with
all subjects experiencing the same levels of clinical symptoms regardless of treatment
24]. Further clinical trails of using hookworm infections in coeliac patients are still
expected.

Helminth therapy and allergy

Another field of much interest in recent years is whether helminth therapy may be
useful in reducing allergic symptoms. Several studies from helminth endemic areas
have suggested that certain helminth infections may protect against allergy and asthma
but a systematic review of 33 published studies concluded that there was no overall
protective effect of helminth infections in general on asthma 25]. However, concurrent hookworm infection was associated with a protective effect,
which was infection-intensity dependent. In contrast, concurrent Ascaris lumbricoides infection, another common intestinal nematode infection, was associated with a significantly
increased risk of asthma. This is particularly interesting given the fact that both
hookworms and Ascaris pass through the lungs during their migration to the intestine but only Ascaris is being known as causing tropical pulmonary eosinophilia syndrome, due to its high
allergenicity 25], thus demonstrating that only certain specific helminth species are likely to be
beneficial from a helminth therapy perspective.

Studies on the relationship between helminth infection and atopy have also generated
mixed results with both positive and negative associations depending on the species
of worms involved 26] and deworming studies in helminth endemic communities have either shown no evidence
for increased skin prick test (SPT) reactivity 27], or increased SPT reactivity 28],29]. However, allergen SPT reactivity may also be influenced by worm infections due to
the fact that many helminth antigens crossreact with common allergens and it may be
that the release of helminth antigens from dying worms after anti-helminthic treatment
may increase reactivity temporarily. In this context it is important to recognize
that several highly immunogenic helminth proteins share structural relationships with
a number of common allergens, for example, IgE cross-reactivity has been demonstrated
between helminth (e.g. filarial and Ascaris) tropomyosins and the tropomyosins of
house dust mite (Der p 10) and cockroaches (Bla g 7) suggesting that helminth infections
may well be able to enhance allergic reactivity. The number of potentially cross-reactive
proteins shared among helminths and allergens has been suggested to be very extensive,
with 40% of 499 molecularly defined allergen families having homologs in helminth
parasite genomes 30]-32].

In the light of a large body of literature suggesting some protective benefits of
helminth infections on allergy and asthma a few human helminth therapy trials in asthma/allergy
have been published. The first one, a randomized trial using 8 doses of TSO, or placebo,
at an interval of 21 days in 100 patients with grasspollen-induced allergic rhinitis
showed no significant effect on rhinitis symptoms, grass-specific IgE levels, or SPT
reactivity, despite inducing T.suis-specific antibody responses and gastrointestinal symptoms 33]. Similarly, a small randomized safety study in individuals with allergic rhinoconjunctivitis
treated with hookworm larvae or placebo, and followed for 12 weeks, reported no significant
effects on lung function, SPT or rhinconjunctivitis symptoms, despite clear evidence
of hookworm-induced responses such as increased eosinophilia and gastrointestinal
symptoms 34]. Another small randomized control trial in patients with asthma again showed no significant
benefit of hookworm infection on clinical symptoms, bronchial responsiveness or SPT
reactivity 35]. It should be noted, however, that both the hookworm studies were small studies with
15 and 16 patients in each group, respectively, and using low doses of larvae (10),
while the timing of infection in relation to pollen season may also need to be adjusted
to reach optimal affects. As such, further trials are required in order to draw any
firm conclusions on the potential benefits in using helminth therapy against allergies
and asthma.

There are a number of potential reasons why the results from human trials have not
generated more positive data. A large number of animal studies have demonstrated a
potent ability of a variety of helminth infections to reduce allergic reactivity in
mice and rats (reviewed in 14]), however the vast majority of studies have shown this as an ability to prevent the
development of allergic reactivity after exposure to helminths, and only a handful
have reported the ability for the infections to impact an already established allergic
reactivity. Furthermore, a few animal studies have also reported the inability of
helminth infections to alter such an established allergic response. As such, most
of the experimental data available suggest that once the allergic reaction is established
helminth infections can do little to alter this, raising the inevitable question whether
there is any true benefit to gain from helminth therapy in already allergic individuals.
Regardless, in terms of the disappointing clinical trials in humans there are still
question remaining surrounding whether optimal timing of treatment, the dose and whether
systemic versus non-systemic infections may play an important part. TSO is entirely
restricted to the intestine and may not induce sufficient systemic response to alter
the environment in the lungs or other parts of the body. The human hookworm Necator however does migrate through the lungs at the early stages of infection but here
the question remains if the dose (10 larvae) is sufficient to induce enough of a response.
Needless to say virtually all animal studies have used significantly higher infection
doses than may be viewed as safe to ever use in humans. Finally, the timing of infection
versus the onset of seasonal allergy may need to be investigated as the immunomodulatory
effect of helminth infection may take longer time to develop than what was measured
in the trials to date. In addition, the use of low dose trickle infections may also
improve immunmodulatory activity over time and warrants further investigation.

Other uses for helminth therapy

Animal studies using the MS mouse model of experimental autoimmune encephalomyelitis
(EAE) has suggested a protective effect of helminth infections on CNS disease progression
36],37] and a prospective study demonstrated that 12 MS patients infected with a variety
of helminth infections had significantly fewer relapses and lower MRI activity when
compared to 12 non-helminth infected MS patients over a time period of 4.5 years 38]. In a follow up study it was further shown than when these patients received anti-helminthic
treatment their clinical presentation deteriorated and this was associated with a
reduction in IL-10 and TGF-?, and an increase in IFN-? and IL-12 secretion from MBP
peptide stimulated PBMCs 39] thus providing further support that helminth therapy may be of some benefit in MS
patients. Subsequently, a phase 1 study for TSO treatment in 5 multiple sclerosis
patients reported fewer new lesions during and up to two months after TSO treatment
as well as increased serum levels of IL-4 and IL-10 40]. Several Phase 1/2 clinical trials using TSO or hookworm in MS patients are currently
registered as recruiting or ongoing (NCT00645749, NCT01413243, NCT01470521). In addition
to MS a number of clinical trials are currently registered for the use of TSO in patients
with psoriasis, autism and rheumatoid arthritis.

Potential for helminth products as new drugs

Helminths secrete a rich mixture of proteins, carbohydrates and lipids, collectively
named excretory-secretory (ES) products, into their surrounding environment and many
of these ES products have been found to exhibit a variety of immunomodulatory activities.
The best characterized product to date is the ES-62 molecule from the filarial nematode
Acanthocheilonema vitae (reviewed in 41]), a glycoprotein with potent ability to skew dendritic cells towards promoting Th2
and inhibiting Th1 and Th17 polarisation. In addition, ES-62 is able to inhibit mast
cell activation and induce IL-10 secretion from B cells and macrophages. ES products
from a variety of other helminths have also been shown to drive Th2 differentiation
and induce de novo differentiation of T regulatory cells, suggesting a therapeutic potential for inflammatory
disorders. Indeed, animal studies have demonstrated that a variety of ES products
can protect against allergen-induced airway hypersensitivity in mice, limiting peri-bronchial
inflammation by inhibiting eosinophil and neutrophil infiltration of the lungs while
increasing T regulatory cell numbers and IL-10 secretion. Moreover, animal studies
have shown the potent ability of various ES products to inhibit intestinal inflammation
in colitis models, the development of Th1-dependent type 1 autoimmune diabetes in
NOD mice, reducing the development of EAE in the mouse model of MS and blocking the
induction of collagen-induced arthritis (reviewed in 41]-43]). Taken together, all this evidence suggests an exciting potential for new drug discoveries
to be made. However, much work remains before such products can be taken to the clinic,
as most of the ES products remain to be characterized in detail and any problems with
potential antigenicity and/or allergenicity needs to be resolved, such as the development
of non-immunogenic mimetics 41].