Innate immunity against cancer
Innovations in cancer immunotherapy have achieved clinical success, significantly increasing the survival rate of patients with cancer. However, there is still an unmet clinical need due to the low frequency of response to checkpoint inhibitors caused by low immune reactivity of cancer cells in "cold" tumors. In their attempts to turn immunologically "cold" tumors into "hot" ones, many pharmaceutical companies have focused on using an innate immune regulatory protein – stimulator of an interferon gene (STING) – to increase the immunoreactivity of tumors and infiltration of immune cells into the tumor microenvironment. But since clinical trials of the first STING agonist, the drug ADU-S100, were suspended in 2020, there is a need to develop new STING activators.
Under these conditions, a research team led by Dr. Sangi Lee from the Institute of Brain Sciences The Korean Institute of Science and Technology and Dr. Hyejin Kim from the Center for Therapeutic Research of Infectious Diseases of the Korean Research Institute of Chemical Technology announced the development of new low-molecular agonists STING (compounds 4a and 4c).
In experiments on mouse models of colorectal carcinoma, new STING agonists 4a and 4c induced cytokine secretion and activated an innate immune response mediated by T cells. The activated immune system changed the immune phenotype of the tumor, turning it from a "cold" with low reactivity to T cells into a "hot" with high reactivity, which led to the accumulation of T cells in the tumor microenvironment.
In this study, the introduction of new STING agonists effectively inhibited the growth of cancer cells in mice. In particular, 20% of the animals in the experimental group demonstrated complete elimination of tumors. In addition, immunological memory suppressed the growth of recurrent tumors without the need for additional drug administration. Ultimately, in mice that had a complete disappearance of the tumor after the first treatment, no signs of re-growth of tumor growth were observed.
Most of the existing STING agonists are injected directly into the tumor, which limits the widespread use of this group of drugs, whereas new compounds 4a and 4c can be administered intravenously. These agents can also be used for combination cancer therapy in combination with standard methods of treatment – radiation and chemotherapy.
This study may serve as a basis for new strategies for the treatment of oncological diseases in cases where immunotherapy has limited use, for example, in brain tumors.
Article by M.J.Jeon et al. The Development of Potential Immune Modulators Targeting Stimulator of Interferon Genes Receptor is published in the Journal of Medicinal Chemistry.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on EurekAlert!: Cancer immunotherapy capable of modulating tumor immunophenotypes.