A novel chimeric switch receptor created at St. Jude Children’s Research Hospital significantly enhanced the effectiveness of chimeric antigen receptor (CAR) T cell immunotherapy in preclinical models of pediatric solid tumors. The research appears today in the journal Cancer Discovery.
The receptor, GM18, takes advantage of normal T cell activation and provides an additional signal to sustain the function of CAR-T cells. The CAR.GM18-T cells proved effective against solid tumors long after standard CAR-T cells have died.
In preclinical mouse models of osteosarcoma and Ewing sarcoma, the tumors shrank and disappeared in more than 90% of cases cell doses at which standard CAR-T cells were ineffective. Osteosarcoma and Ewing sarcoma are pediatric solid tumors. Outcomes have not improved for two decades for patients whose tumors have recurred or metastasized.
“The GM18 receptor also allowed CAR-T cells to function after repeated re-exposure to tumor cells, which had previously limited the effectiveness of the immunotherapy in treatment of solid tumors,” said corresponding author Stephen Gottschalk, M.D., chair of the St. Jude Department of Bone Marrow Transplantation and Cellular Therapy.
Immunotherapy and solid tumors
CAR-T cell therapy involves collecting and genetically modifying the patients’ own T cells to enhance their ability to recognize and kill tumor cells. The cells are expanded in the laboratory and infused back into patients.
The immunotherapy has transformed the treatment landscape for leukemia, lymphoma and other blood cancers. But CAR-T cell therapy has faced more challenges and been less successful against solid tumors in adults and children. The obstacles include the tumor microenvironment that suppresses the immune response and limits the ability of CAR-T cells to expand and persist.
GM18: Designed to withstand the tumor microenvironment
“To address the challenge, we took naturally occurring human molecules and combined them to create a signaling loop that sustains CAR-T cell function in the harsh tumor microenvironment,” Gottschalk said. The goal of Gottschalk and his colleagues was to activate the MyD88 signaling pathway, which plays a critical role in immune responses.
GM18 was created to do that job. Activated T cells secrete a signaling molecule (cytokine), GM-CSF, but lack the necessary receptor to bind and respond to GM-CSF. To create GM18, researchers now combined the extracellular components of the GM-CSF receptor with the intracellular components of another cytokine receptor, IL-18, which signals through MyD88.
The novel receptor is activated by GM-CSF and then works through its IL-18 receptor portion to activate MyD88. That leads to production of a variety of molecules that sustain T cell growth and enhance T cell antitumor response.
“CAR.GM18-T cells were able to work in the tumor microenvironment to expand and kill tumor cells,” Gottschalk said. “Cells with the novel receptor were more than 10-fold more effective than standard CAR-T cells.”
CAR.GM18: next steps
Work is underway to streamline production of CAR.GM18-T cells. Additional preclinical testing is also planned to assess the safety and effectiveness of GM18 in preclinical pediatric solid tumor models.
The first authors are Shannon Lange, Ph.D., of St. Jude, and Laurens GL Sand, Ph.D., formerly of St. Jude. The other authors are Matthew Bell, Sagar Patil and Deanna Langfitt, of St. Jude.
The research was supported in part by Alex’s Lemonade Stand Foundation and ALSAC, the St. Jude fundraising and awareness organization.
St. Jude Children's Research Hospital
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