Newsletter Signup - Under Article / In Page
"*" indicates required fields
In the vast field of immunotherapy, toll-like receptor agonists (TLR) emerged as powerful catalysts to boost the immune system. This class of drugs is designed to mimic the body’s natural defense mechanisms and target a spectrum of diseases – from cancer and infectious diseases to conditions like radiation poisoning. However, despite some of them receiving approval from regulators, uncertainty lies in whether they are truly beneficial in combating pathogens and harmful agents. In this article, we take a look at some of the TLR agonists in the clinic and why the careful selection of these drugs is crucial.
Table of contents
How do TLR agonists work?
Toll-like receptors (TLRs) are a family of proteins that play an integral part in the immune system, as they are the first line of defense against pathogens and harmful cells. These proteins are present in immune cells, from where they recognize foreign and detrimental substances, and they serve as a bridge between innate and adaptive immunity. So, you can imagine these proteins are quite crucial for the well-being of cells in the body.
Stimulating these proteins to trigger an immune response can help orchestrate antitumor immunity in the case of cancer, as well as battle viral infections. That’s where TLR agonists come in. These agonist drugs bind to TLRs, which go on to identify pathogens and abnormal cells like cancer cells. TLRs begin a signaling cascade that leads to the production of molecules, such as cytokines, which act as messengers to regulate inflammation and immune responses.
The U.S. Food and Drug Administration (FDA) has approved a handful of TLR agonists, one of which is imiquimod. It is a topical cream prescribed for people with superficial basal cell carcinoma, a type of skin cancer. Imiquimod activates specific TLRs, namely TLR7 and TLR8, to produce cytokines and recruit immune cells against cancer cells. The drug also incites the death of these target cells.
Two other TLR agonist therapies that have been cleared by the FDA are actually vaccines with adjuvants. An adjuvant is a substance that is added to vaccines to amplify the immune response. The bacillus Calmette-Guérin (BCG) vaccine for tuberculosis – a highly infectious disease that affects the lungs – is also an immunotherapy for people with bladder cancer. BCG switches on TLR2 and TLR4 so that the immune system can destroy the cancer cells in the lining of the bladder.
The other FDA-greenlit therapy containing a TLR agonist is MPLA, which stands for monophosphoryl lipid A, a TLR4 ligand derived from the bacteria Salmonella minnesota. MLPA is an adjuvant used in several vaccines, including ones for human papillomavirus (HPV), a common cause of cervical cancer.
Although there are only three TLR agonists that have received the go-ahead from the FDA, there are a few in the clinic directed towards various TL receptors.
TLR agonists: a player in the chronic hepatitis B therapeutic space
British pharma giant GSK’s GSK5251738 is a TLR8 agonist targeting chronic hepatitis B virus (HBV) infections, which is currently in phase 1 trials. Hepatitis B is a serious liver infection that is caused by HBV. Around 254 million people live with hepatitis B, and 6,000 people are newly infected with viral hepatitis each day, according to the World Health Organization (WHO).
Restoring HBV-specific immune responses is central to achieving a cure for chronic hepatitis B, according to Bluejay Therapeutics. The California-based biopharma is developing cavrotolimod, a spherical TLR9 agonist that is designed to trigger innate and adaptive immune responses by binding to and activating the protein TLR9. In phase 1a/1b trials at the moment, the drug selectively activates dendritic cells and B cells to set off antiviral immune responses.
Preclinically, cavrotolimod exhibited “a potent TLR9 activation profile,” wherein it induced a cytokine response in white blood cells. Moreover, in an animal study, it was able to do the same, proving its ability to induce an antiviral reaction and potentially treat HBV.
Like cavrotolimod, there are actually various TLR agonists in the clinic to treat HBV. Apros Therapeutics’ APR003 is another one and it is also being tested to treat liver cancer. The oral drug is a TLR7 agonist designed to localize to the gastrointestinal tract and liver to expedite immune cell activation in targeted tissues. In the case of HBV, it turns on the innate immune system, specifically the type I interferon response, to take over the reins of the virus.
TLR agonists tested to treat solid tumors: will they succeed?
On the other hand, in liver cancer, TLR7 activation in the liver is thought to result in innate immune priming – the process where the innate immune system, when exposed to a tumor, becomes more responsive – the release of cytokines and, ultimately, enhanced anti-tumor immune responses.
TLR7 agonists in particular are rather popular in the space. TLR7 mainly recognizes viral genetic material, specifically single-stranded RNA, explained a 2023 report on the TLR clinical landscape by Nature. This recognition spurs an immune response, primarily in certain dendritic cells called plasmacytoid dendritic cells (pDCs) – immune cells known for their high production of signaling proteins like interferons in response to viral infections – which are essential for initiating antiviral defenses.
American biotech Eikon Therapeutics has a clinical candidate that is an agonist of both TLR7 and TLR8. The two receptors are often paired together as targets when developing TLR agonist therapies. This is because agents that bind to TLR7 also do so with TLR8, a double-win when it comes to developing agonist drugs, because of their shared phylogeny – the evolutionary history of a group of organisms, but in this case, molecules types in cells. This is because the two recognize similar viral single-stranded RNA and are both located within endosomal compartments of cells – the region that sorts the materials going in and out of cells.
Eikon’s TLR7- and 8-focused agonist aims to address two kinds of cancers, non-small cell lung cancer (NSCLC) and melanoma, a type of skin cancer. EIK1001 works by stimulating myeloid and plasmacytoid dendritic cells to initiate immune and inflammatory responses. A phase 1 biomarker analysis revealed that the therapy showed heightened efficacy as well as dose-dependent increases in patients with solid tumors.
EIK1001 is being developed as a potential alternative to checkpoint inhibitors and even in combination with them. While checkpoint inhibitors relieve the immunosuppression of tumor-reactive T cells and enhance antitumor immune response, not all patients benefit from them, and some become resistant and stop responding to treatment. So, the team at Eikon believes that activating toll-like receptors provides another pathway that is distinct from effects on checkpoint proteins in order to enhance antitumor T-cell activity.
To further support its drug pipeline, which is anchored by EIK1001, the biotech raised over $350 million in a series D financing round in February.
The TLR-checkpoint inhibitor combination is being evaluated by TriSalus Life Sciences as well. TriSalus’ drug nelitolimod, also known as SD-101, is currently in phase 1 studies along with checkpoint inhibitors to treat liver cancers.
Why aren’t there more TLR agonists in development?
Although there are some TLR agonists being developed, as seen above, many struggle to progress through clinical trials owing to various challenges. These hurdles include the risk of unforeseen inflammation, especially since the primary role of TLR agonists is to activate the immune system.
While several drug candidates were in the clinic back in 2023, according to the Nature report, many of these studies have fizzled out, and the biotechs linked to these drugs have placed safer bets in the field of cancer therapeutics. For example, tilsotolimod, a TLR9 agonist, was dropped by its developer Idera Pharmaceuticals, which later merged with U.S.-based Aceregen. As for CureVac’s development of the TLR 7/8 agonist CV8102 as a monotherapy, it was limited to potential combination studies with mRNA cancer vaccines only three years ago.
Moreover, there is a need for the careful selection of agonists because some TLRs have even been found to worsen tumor growth and metastasis, according to a research paper published in the IUBMB Journals. In fact, a report by the National Institutes of Health (NIH) refers to TLR agonists as a “frenemy in cancer immunotherapy.” This is partly because, on occasion, this class of drugs has been linked to promoting cancer cell growth, and as a monotherapy, their efficacy has been limited.
Tivic Health’s TLR acquisition shakes technological space
Still, biotechs like Eikon Therapeutics and Bluejay Therapeutics, as well as big pharmas like GSK, anticipate potential success in the clinic. Moreover, only two months ago, California-based Tivic Health bought the worldwide rights of the TLR5 agonist entolimod for the treatment of acute radiation syndrome (ARS), known more commonly as radiation poisoning, from Colorado-based Statera Biopharma. Animal studies have shown that entolimod led to a three-fold increase in survival after exposure to lethal levels of radiation.
Besides, if three therapies including vaccine adjuvants have been endorsed by regulators, there must be something to this technology, and we will have to wait and see how they fare in future studies.
Technological advancements related to TLR agonists
- Novel Toll-Like Receptor (TLR) 7/8 Agonist Antibody-Drug Conjugates – SUNY Research Foundation
- Rationally Designed Human TLR8-selective Agonists – University of Kansas
- Adaptive Immune Response Stimulated with TLR8 and Dual TLR7/TLR8 Agonists – University of Minnesota
Oncology R&D trends and breakthrough innovations
