Immune Activation Advances Hold Promise for Immuno-Oncology

Immune Activation Advances Hold Promise for Immuno-Oncology

Immuno-oncology has largely changed the landscape of cancer care, but a number of challenges still exist. From judging efficacy to understanding why some people react to the treatment while others do not, researchers are tackling a number of issues. One young startup in Europe is attempting to address the latter question. At present, only about 20 to 30 percent of patients respond to immunotherapy. Sylvain Carlioz and Nicolas Manel, both of whom worked at Institut Curie in Paris, believe that they may have a way of “activating” a patient’s immune system to make it more responsive to cancer. Manel has patented the technique, which has already appeared in two papers in Science published through the University of Oxford.

Stimunity focuses on the “stimulator of interferon genes” (STING) pathway, which induces type I interferon production, which in turn activates the innate immune system. Through the STING pathway, Stimunity hopes to provoke the patient’s immune system into fighting cancer, which could also make the body more responsive to immunotherapies.

STING triggers a response in dendritic cells that starts a response from cytotoxic T lymphocytes against infectious pathogens. While scientists have long understood this pathway, they have had trouble activating it. The STING pathway is intracellular and small molecules capable of activating it are unable to penetrate cell membranes. Past efforts have used high doses and local injections with inconsistent results. However, Stimunity believes it has engineered a better way of delivering the drug.

The STING pathway stimulates the production of TBK1, which phosphorylates IRF3 or STAT6. Then, these phosphorylated molecules enter the nucleus of the cell to express genes involved in the host immune response, including CCL2, CCL20, and IFNB. Research also suggests that STING plays a role in activating selective autophagy, as shown by studies of the tuberculosis bacterium in the body. Thus, STING may play a role in multiple immune responses to pathogens. In addition, as the name of the pathway suggests, STING triggers the release of interferons, which inhibit the replication of pathogens.

By using a virus-like particle (VLP), Stimunity has turned cGAMP, a proven STING activator, into a vector that can pass through the cell membrane. By using a vector, the company has achieved remarkable rates of STING pathway activation. Vectors target specific cells, and Stimunity has engineered viruses that target dendritic cells and/or tumor cells with specific fusion proteins. These proteins allow the virus to penetrate the cell membrane and stimulate the STING pathway. Importantly, the virus membrane actually protects the cGAMP inside from extracellular degradation. This enables systemic administration of the drug. Stimunity’s technique has apparently distinguished  itself from competitors with in vitro and in vivo preclinical data that shows the same level of activation as existing therapies—but with a dosage that is 1,000 times lower.

Despite these promises, the company clearly faces some challenges. Scaling manufacturing is difficult for nearly all biotechnology startups, and the creation of large quantities of the Stimunity virus will be no different. In addition, the company still faces human trials and the possibility of serious side effects from the treatment. Some immunomodulators that have shown excellent results in animals have actually proven poisonous in humans due to extraordinarily high inflammation. However, because Stimunity uses such a low dose to achieve its results, the effects on the body may be minimal.

Stimunity is not the only company targeting the STING pathway as a means of jumpstarting the immune system. One of the company’s primary competitors is the Silicon Valley startup Aduro Biotech, which recently inked a $750 million deal with Novartis for the development of a chemically stabilized cGAMP that is still in the preclinical stages. Novartis offered such a large sum to the company because of the extraordinary promise of the STING pathway in supporting the efficacy of its immune checkpoint and CAR-T treatments.

In addition, Novartis has paid Aduro $200 million up front for the cyclic dinucleotides naturally expressed by bacteria and immune cells that trigger the STING pathway. Aduro will receive $500 million in milestone payments over the coming years of the partnership with Novartis, which also has a 2.7 percent stake in the startup after making a $25 million investment with another $25 million promised.

Aduro’s treatment is very similar to Stimunity’s, but it relies on a different pathway that requires localized administration and much higher doses—at least for the time being. For that reason, Stimunity may have a leg up on its competition, although it lacks the support of a major immuno-oncology player like Novartis.

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