Activating an immune signaling pathway known as STING, which is best known for fighting viral and bacterial infections, may improve the ability of genetically engineered T cells to eradicate breast cancer in mice, according to a recent study by University of North Carolina (UNC) researchers reported study. Their results, published in the Journal of Experimental Medicine, suggest that chimeric antigen receptor (CAR) T cells, which are already used to treat certain types of blood cancers in humans, can also be effective against solid tumors in combination with other immunotherapeutic approaches.
« We know that CAR-T cells are safe for patients with solid tumors, but so far they have not caused significant tumor regression in the vast majority of people treated, » said Jonathan S. . Serody, MD, Elizabeth Thomas Professor of Medicine, Microbiology, and Immunology and Director of the Immunotherapy Program at UNC Lineberger Comprehensive Cancer Center. “Now we may have a new approach to make CAR T cells work in solid tumors. We believe this could play a crucial role in therapies that target a significant number of cancers. In their published article entitled « STING Agonist Promotes CAR T Cell Trafficking and Breast Cancer Persistence, » the author Serody and colleagues concluded: « To the best of our knowledge, these data are the first to demonstrate the function of a demonstrate STING agonist in altering the commercial properties of adoptive T cell products. ”
CAR T cells are a type of white blood cell that has been genetically engineered to recognize and attack cancer cells that express certain proteins on their surface. CAR T cell treatments have been used successfully to treat patients with B cell lymphoma and are currently in clinical trials for the treatment of many other types of blood cancers. « However, the clinical activity of CAR-T cells in patients or animal models with solid tumors has been modest, » said Serody, director of the cell therapy program at the University of North Carolina School of Medicine.
CAR-T cells may be less effective against solid tumors because they migrate into tumors and then have to survive long enough to kill all tumor cells. In addition, the cells and molecules surrounding tumors are often immunosuppressive and activate an immune checkpoint that causes the CAR T cells to lose their activity.
When treating patients with non-solid tumors such as lymphoma, CAR-T cells are found in the bone marrow and other organs that make up the lymphatic system. However, this is usually not the case with solid tumors such as breast cancer. And even if they migrate to the tumor, due to the nature of the microenvironment that surrounds such tumors, they don’t persist and expand there well, Serody noted. « Potential obstacles to the effectiveness of CAR-T cells against solid tumors include sub-optimal migration and persistence of CAR-T cells in the tumor microenvironment (TME), immunosuppressive TME-mediated dysfunction, and depletion of CAR-T cells « explained the authors.
For their newly reported research, Serody and colleagues were looking for ways to target laboratory-expanded cells to the sites of solid tumors. They focused on generating CAR T cells from Th17 and Tc17 cells, which are known to have longer persistence in the microenvironment surrounding a tumor, in part due to their better survival abilities. « Th17 cells and their counterparts Tc17 cells (CD8 T cells that express IL-17A) have longer persistence in TME, partly due to their better survival in vivo, » the team noted.
The researchers tested various strategies to increase the effectiveness of CAR T cells in a mouse model of breast cancer. With the aim of increasing the accumulation of Th17 and Tc17 cells near solid tumors, they turned to two small molecules – the stimulator of the interferon gene (STING) agonists – DMXAA and cGAMP, which activate an immune response can.
The STING pathway is a signaling pathway for immune cells that normally causes inflammation in response to invading viruses or bacteria. In their experimental setting, the researchers showed that activation of the STING signaling pathway creates a pro-inflammatory environment within the mouse tumors and improves the ability of the CAR-T cells to accumulate and attack the tumor cells. « The most compelling finding was the ability of the STING agonists DMXAA and c-GAMP, administered at a site remote from the tumor, to promote the recruitment and persistence of CAR T cells at the tumor site, » the team explained. « CAR T cells generated from Th / Tc17 cells administered with the STING agonists DMXAA or cGAMP greatly improved tumor control . . . « .
The accumulation was particularly large when the mice were infused with CAR-T cells, which produce the immune signaling molecule IL-17A, compared to CAR-T cells generated using standard techniques.
Serody and colleagues found that CAR T cell attack could be sustained for longer periods of time if the mice were also treated with therapeutic antibodies that remove immunosuppressive cells from the tumor environment and prevent the immune checkpoint deactivated the CAR T cells. The combination of all these approaches resulted in the complete eradication of breast tumors. « . . . sustained tumor regression was only achieved by adding anti-PD-1 and anti-GR-1 mAbs to Th / Tc17-CAR-T cell therapy with STING agonists, ”the researchers wrote.
The team suggested that their results suggest a « workable strategy » for increasing CAR T activity in solid tumors. And while DMXAA, which worked well in the investigator’s mouse studies, has been of no benefit in human clinical trials because it does not activate the human STING, the second STING agonist, cGAMP, activates the human STING and is known to boost the human immune system.
“cGAMP is in clinical trials for the treatment of cancer patients. There are several ongoing clinical trials using approaches to inhibiting immunosuppressive cells in patients with malignant disease, and there are clinical trials currently investigating the combination of CAR T cells with immune checkpoint blockade, ”Serody said. “Therefore, our data together suggest a viable strategy for increasing CAR T activity in solid tumors. We hope to be able to study cGAMP in humans soon. We will look to see if we can make improvements in head and neck cancer treatment first, and if that proves promising, we can use CAR T cells made by one of our colleagues here at UNC to feed on others Switching cancers. ”
Chimeric Antigen Receptor, Neoplasm, Breast Cancer, Immunotherapy, Cell, Research
World News – AU – Strategy to increase the effectiveness of CAR T cells against solid tumors in mice
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