According to a new study by University of North Carolina researchers, activating an immune signaling pathway best known for fighting viral and bacterial infections can improve the ability of genetically engineered T cells to eliminate breast cancer in mice.
The research, published in the Journal of Experimental Medicine (JEM) on Dec. 31, 2020, indicates that, when paired with other immunotherapeutic methods, CAR-T cells, already used to treat some human blood cancers, may also be effective against solid tumors.
A type of white blood cell that has been genetically engineered to recognize and attack cancer cells that express certain proteins on their surface is chimeric antigen receptor (CAR) T cells.
They have been successfully used in the treatment of B-cell lymphoma patients and are now in clinical trials to treat many other forms of blood cancers. “However, the clinical activity of CAR T cells in patients or animal models with solid tumors has been modest,” says Jonathan S. Serody, the Elizabeth Thomas Professor of Medicine, Microbiology and Immunology and director of the Cell Therapy Program at the University of North Carolina School of Medicine.
Against solid tumors, CAR-T cells may be less effective because they must first migrate into tumors and then live long enough to destroy all tumor cells. In addition, the tumor-surrounding cells and molecules are also immunosuppressive and activate an immune checkpoint that causes their activity to be lost by CAR T cells.
Serody and colleagues tested multiple methods in the new study to improve the efficacy of CAR T cells in a breast cancer mouse model. Simultaneously treating the mice with drugs such as cGAMP that activate the STING pathway, an immune cell signaling pathway that typically causes inflammation in response to invading viruses or bacteria, was one successful technique.
A proinflammatory environment in mouse tumors was created by the activation of the STING pathway, which increased the ability of CAR T cells to accumulate and invade tumor cells.
The accumulation was especially high when the mice were infused with CAR T cells producing the immune signaling molecule IL-17A, compared with CAR T cells produced using standard techniques.
Serody and colleagues noticed that when the mice were also treated with therapeutic antibodies that exclude immunosuppressive cells from the tumor environment and avoid the immune checkpoint from disabling the CAR T cells, the CAR T cell attack was maintained longer.
The researchers found that the combination of all these methods resulted in the breast tumors being completely eradicated.
According to Serody, “cGAMP is in clinical trials for the treatment of patients with cancer, there are several ongoing clinical trials with approaches to inhibit immunosuppressive cells for patients with malignancies, and there are clinical trials currently investigating the combination of CAR T cells with immune checkpoint blockade,” “Taken together, therefore, our data suggest a viable strategy for enhancing CAR-T activity in solid tumors.”
Nuo Xu, Douglas C. Palmer, Alexander C. Robeson, Peishun Shou, Hemamalini Bommiasamy, Sonia J. Laurie, Caryn Willis, Gianpietro Dotti, Benjamin G. Vincent, Nicholas P. Restifo and Jonathan S. Serody, Journal of Experimental Medicine, 31 December 2020, DOI: 10.1084/jem.20200844. Reference: “STING agonist promotes CAR T cell trafficking and persistence in breast cancer”