Artificially designed proteins may be able to boost the production of immune cells, particularly T cells that fight cancer and harmful infections, according to new research from Harvard Medical School and Boston Children’s Hospital.
The work, conducted in laboratory equipment and mice, offers promise for more efficiently and effectively developing T cells for use in cancer immunotherapies and in vaccines against dangerous viruses or other infections.
The federally supported study is published in Cell.
The scientists used AI technology to design proteins that would activate a cell signaling language called Notch, which is essential for transforming immune cells into T cells. They then successfully used the proteins to generate large quantities of T cells in liquid suspension culture in a laboratory bioreactor rather than on a flat surface.
This marked an important advance, given the growing demand for T cells in hospitals worldwide for use in chimeric antigen receptor T-cell (CAR T) immunotherapies for cancer, the authors said. CAR T-cell treatments currently require the retrieval, modification, multiplication, and reintroduction of T cells into patients to fight cancer.
“Being able to activate Notch signaling opens up tremendous opportunities in immunotherapy, vaccine development, and immune cell regeneration,” said first author Rubul Mout, HMS research fellow in pediatrics at Boston Children’s.
Previously, researchers activated Notch signaling — and in turn increased T-cell production — in the laboratory by immobilizing Notch surface proteins in culture dishes. However, this method can’t be used to produce therapies for humans, which prompted the team to look for another approach.
Led by senior author George Q. Daley, HMS dean and the HMS Caroline Shields Walker Professor of Medicine at Boston Children’s, the researchers took advantage of Rosetta and other AI tools that can computationally design proteins from scratch. They used the tools to develop a library of custom-designed Notch-activating proteins. Then they synthesized those proteins.
In human stem cells in a dish, the synthetic proteins activated Notch signaling and supported T-cell development and function.
Additionally, when the researchers vaccinated mice and added the proteins, the animals had better T-cell responses. Notably, the treatment increased production of memory T cells, which are crucial for long-term impact of vaccines.
“We’ve exploited [AI-driven protein design] to develop a synthetic molecule that facilitates T-cell manufacture for clinical use and enhances immune responses when delivered in vivo,” Daley said.
Daley and Mout added that the team is excited that the approach can guide T cells to tumors, stimulate their cancer cell-killing abilities, and overcome immune suppression by the tumor microenvironment.
Mout, who trained in the lab of Nobel Prize-winning co-author and Rosetta creator David Baker, is especially enthusiastic about the technology’s far-reaching potential.
“Our goal is to develop next-generation immunotherapies and cancer vaccines,” he said.
Source: HMS