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Novel Approaches to Immunotherapy: Immunomodulation

SLIT Is Not the End of Pharmacotherapy for Allergies
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Thomas Casale, MDFor anyone who fears that sublingual immunotherapy (SLIT) will be the final frontier of immunotherapy, Thomas Casale, MD, Chief of Allergy, Creighton University, Omaha, NE, says, think again. A number of other exciting novel agents are in development.

“Yes, SLIT will be in the US,” Dr Casale said during a symposium at ACAAI 2010. “But some of these molecules will change what we all do in immunotherapy, and it will be important for us to keep up with the immunology of allergic response, so we can understand and be the experts in using these and managing adverse events.”

The 4 broad categories of the novel immunotherapy approaches include adding omalizumab, toll-like receptor (TLR) agonists, and chemical and molecular modifications.

The goal of immunomodulation is to reduce or stop the pathologic immune response rather than return the patient to the immunologically naïve or unresponsive state, he said. “The only immunomodulator that we currently have is immunotherapy,” he said, “which has been shown to meet these criteria.” Subcutaneous immuno - therapy (SCIT) has come under fire, because of its serious potential for adverse events.

Adding Omalizumab
A number of studies show that pretreatment with omalizumab adds efficacy and safety to SCIT and allows more patients to reach maintenance. However, questions remain, including the length of time needed to treat, and whether omalizumab can be safely stopped after reaching maintenance immunotherapy.

TLR-4 Agonists
There are probably a total of 13 TLR ligands in humans, 11 of which have already been identified, he said. The monophosphoryl lipid (MPL) A TLR-4 agonist has been around since the 1970s, and is used in Europe in an ultrashort-course vaccine for seasonal allergic rhinitis (AR), grass, tree, or ragweed, although “at the time, nobody knew that MPL was actually a TLR-4 receptor agonist,” Dr Casale said.

A number of studies have shown that 4 preseasonal injections of this will reduce symptoms and medication use, elevate antigen-specific immunoglobulin (Ig)G, and blunt the seasonal elevation of IgE.

In a 2010 study by Pfaar and colleagues, after 10-week SLIT and MPL A TLR-4 agonist treatment, patients who received the highest doses of MPL had more than a 2-fold better inhibition of nasal allergen challenge responses. “So, we’ll have to see if even using SLIT with MPL or a toll-4 receptor agonist might be a way to go in the future,” Dr Casale said.

CpG Molecules: TRL-9 Agonists
CpG molecules, the TLR-9 agonists, were also celebrated in the past. One in particular (Tolamba) seemed promising, but a clinical studies problem led to its discontinuation. Cytos Pharma ceuticals has recently tried a new paradigm.

“Cytos took a CpG molecule and put it in a virus-like particle. This is injected and transported to the lymph node, where the protein shell is degraded, and the CpG molecule is released, with activation of toll-9 receptors,” Dr Casale said.

A 2010 study showed that the combination of this molecule with the house dust mite led to “a nice improvement,” Dr Casale said. “But the interesting thing to me is that after stopping treatment at 10 weeks, you had a sustained effect for 48 weeks.”

Just using the CpG molecule and the virus-like particle in patients with asthma brought a 50% reduction in symptoms after 4 weeks. There was also a continuous improvement in symptom scores, even though the patients were no longer taking corticosteroids. After the corticosteroids were halved and then cut, patients using this molecule maintained their forced expiratory volume in 1 second.

This molecule improved objective and patient-reported outcomes in AR and asthma, he said. It may also have steroid-sparing and anti-inflammatory effects, and two thirds of patients had well-controlled asthma even after steroid discontinuation. This agent acts through an allergen-independent mech anism and not through an adjuvant effect. Treatment was safe and well tolerated.

TLR-8 Agonists
“If you want to inhibit allergic responses, what you want to do is to generate a cytokine profile that will do that more efficiently,” Dr Casale said. “And that really occurs with TLR-8 agonists.”

A first-in-man study of 4 administrations of TLR-8 receptor agonists, given once weekly, used intranasal active treatment, after which patients were placed in a grass allergen chamber for 6 hours. Total nasal symptom scores were significantly improved; total ocular symptom scores im - proved almost significantly; and rhinometry trended toward improvement, as well. “So, another approach is using weekly intranasal TLR-8 agonists,” Dr Casale said.

Depigoids
Dr Casale then discussed ways to use allergen immunotherapy by changing the molecule slightly to make either recombinant allergens or peptide allergens. One example is depigoids, a depigmentation and polymerization of allergen into a pure allergoid or polymerized allergen. The 2010 Depigoid birch study measured the effect of Depigoid treatment in patients allergic to birch pollen immunotherapy. As the pollen count went up, the increase was blunted in patients treated with Depigoid.

“So, a different way of doing the immunotherapy, a little less onerous,” Dr Casale said.

Recombinant Peptides
Several recombinant peptides are in development, said Dr Casale. Because there are no B-cell epitopes in the peptides, there is no need to dose-escalate. This should result in a safer product that is broadly applicable across a range of allergies.

A recent study compared the cat antigen ToleroMune single injection with house dust mite weekly injection, birch whole allergen, or grass sublingual. At the end of 4 days of challenge to cat allergen in an environmental exposure chamber, patients had a marked reduction in rhinitis symptoms, suggesting that with in - creasing antigen load, they had improved efficacy.

“It appears that peptides manufactured synthetically allow for better dose standardization,” Dr Casale said. “You don’t need dose escalation; you have a room-temperature stable formulation. The safety profile looks good. A short course of immunotherapy over 3 months is what they would recommend; and they’ve shown you actually have clinical efficacy with 4 administrations,” he said.

“Ultimately, what we want to do is provide better therapeutic options with decreased symptoms, improved quality of life, and immunomodulation, where you could prevent or alter the disease course. And of course you want to do this where it’s cost-effective, and that’s been a problem with monoclonal antibodies.”

He concluded, “I think the future is getting closer and closer.”

Last modified: August 30, 2021