Immunotherapy is a very broad term. It can mean activating the immune system to fight or prevent disease, priming the immune system to work in a certain way or utilizing existing components of the immune system as part of a treatment’s mechanism of action. There is considerable potential for activating the immune system, especially by stimulating toll-like receptor 7 (TLR7) to treat cancers and infectious diseases.
Often referred to as sentinel molecules, toll-like receptors detect the presence of an infection and initiate an immediate response as well as a downstream, long-lasting response. The immediate response includes the secretion of cytokines such as interferon-alpha that can block virus replication and kill malignant cells. The downstream responses include activation of certain cellular components of the immune system, including natural killer cells and cytotoxic T lymphocytes.
Recombinant interferon-alpha products are approved for a wide variety of indications, including hepatitis C (HCV) and B (HBV) and certain cancers, although only a fraction of treated patients show complete and durable responses. Higher doses cannot be explored to increase response rates due to dose-limiting intolerabilities of the interferon treatment, including fever, chills, other “flu-like” symptoms, psychiatric, and gastrointestinal side effects.
On the other hand, induction of interferon production through appropriate activation of TLR7 can avoid these same challenges. Downstream interferon-dependent responses have been observed in studies of TLR7 agonists in the absence of the tolerability challenges seen with the recombinant products. This leads researchers to believe that it may be possible to improve upon the therapeutic benefits of interferon by being able to achieve higher pharmacological response before encountering tolerability limits.
For example, the current standard of care for HCV infection is interferon-alpha combined with ribavirin, but patients have significant problems tolerating this treatment. As a result, only a small percentage of patients eligible for treatment seek it or comply with the regimen. In clinical trials in HCV infected patients, TLR7 agonists have demonstrated short-term decreases in virus levels comparable to the decreases seen with interferon-alpha over similar time periods.
All the same, no TLR7 agonists have been successful beyond early stage clinical development due to either clinical intolerability or potential safety concerns. However, recent animal studies conducted at Anadys employing every-other-day dosing have shown that the beneficial immune induction can be achieved without adverse toxicology. There is hope that these findings will represent the breakthrough required for investigating the benefits of long-term TLR7 activation in HCV-infected patients.
While a great deal of attention has been focused on developing direct antivirals for treatment of HCV, no agent has demonstrated long-term clinical benefit except as part of an interferon-based regimen. While future regimens combining multiple, direct-acting antivirals may avoid interferon, this potential has not yet been demonstrated and does not appear to be imminent. Because a TLR7 agonist offers the potential to provide the benefits of interferon products without the limiting side effects, such a treatment may provide an appropriate complement to future direct antivirals.
In oncology, the opportunity for using TLR7 agonists arises from the cytokine induction and activation of cellular components of the immune system that mimic the effects of interferon, creating the potential to treat interferon-responsive tumors. In addition, activation of NK cells following interferon induction also creates opportunities to combine TLR7 agonists with certain monoclonal antibodies. By activating the NK cell population, it may be possible to enhance the effectiveness of these monoclonal antibodies.
TLR7 is also expressed in B-cells, leading to an opportunity to treat B-cell diseases such as non-Hodgkin’s Lymphoma and chronic lymphocytic leukemia. In non-malignant B-cells, activation of TLR7 leads to cellular maturation and proliferation, as part of the natural, coordinated response to infection. However, in malignant B-cells, activation of TLR7 promotes apoptosis and sensitizes these cells to the action of certain cytotoxic treatments.
Activating TLR7 can also shift the balance between certain cell subpopulations in the immune system, especially augmenting the ratio of TH1 to TH2 cells, subpopulations of helper T-cells. It is believed that certain diseases outside of oncology and infectious disease, such as asthma, can be treated by shifting this ratio.
Researchers have been trying to establish immunotherapies for many years. There have been challenges, specifically when dosing with TLR agonists. However, with a better understanding of how to optimize the schedule of administering TLR7 agonists in different disease states, researchers hope to sculpt the immune response appropriately for different diseases. These efforts build on the results of preclinical and clinical results over the last several years and will hopefully lead to greater clinical success in the coming years.
About the Author
Worland joined Anadys as chief scientific officer in 2001 and has also served as executive vice president, head of research and development, and executive vice president, pharmaceuticals. Previously, he held numerous positions at Agouron Pharmaceuticals and had global responsibility for anti-infective strategy for Warner-Lambert following the company’s acquisition. He holds a bachelor’s degree in biological chemistry and a doctorate in chemistry.
Published online, October 7, 2008
Filed Under: Drug Discovery