CAR-T cell therapy, which modifies a patient’s own T cells to recognize specific antigens on tumors, has proven effective in treating blood cancers. But the engineered immune cells have precious little time to proliferate in the body, which often limits their anti-tumor efficacy. Now, scientists at the Curie Institute in France have identified a potential mechanism that could be targeted to improve T-cell therapies.
By using genomewide CRISPR-Cas9 screen in mice, the Curie Institute team pinpointed the protein SOCS1 as an important “brake” that inhibits the expansion and survival of CD4+ T cells, according to results published in Science Immunology.
Crippling SOCS1 in human CD19-targeted CAR-T cells markedly improved the persistence of CD4+ CAR-T cells and the function of CD8 CAR-T cells in a mouse model. Thus SOCS1 inhibition could boost the efficacy of T-cell therapies against cancer, the team suggested.
When cancer relapses or progresses after patients initially respond well to CAR-T treatments, the culprit is thought to be poor persistence of the engineered cells. One of the key components of CAR-T cell therapy, CD8+ T cells, can continuously self-proliferate after stimulation. But another critical element, CD4+ T cells, require repeated antigen stimulation to continue growing.
To understand the inhibitory mechanism of CD4+ T cells, the Curie Institute team used CRISPR screening to search for genes that, when inactivated, would restore the proliferation of antigen-experienced CD4+ T cells.
The gene encoding for SOSC1 emerged as a hit. In two different TCR CD4+ T-cell models, inactivating the gene helped the T cells expand, while the the proliferation of untreated cells quickly stopped, the researchers reported.
Further analysis showed that SOCS1 moderates the immune system, blocking several signaling pathways and crippling CD4+ T cell proliferation.
The researchers challenged mice with a type of bladder tumor and treated them with anti-tumor CD4+ T cells. Treatment with T cells that had SOCS1 inactivated rejected the tumors, as the T cells proliferated. The researchers also found that the SOCS1-deleted T cells infiltrated tumors more efficiently than control cells by nearly tenfold.
SOCS1 also played a role in regulating CD8+ T cells, the study found. In mice with melanoma, the scientists observed a significant and durable rejection of tumors in animals that received SOCS1-deleted, tumor-specific CD8+T cells as compared with control T cells. In SOCS1-inactivated T cells that entered tumors, the researchers found higher numbers of cytotoxic molecules and effector T cells, likely explaining the strong anti-tumor effect, they said.
The French team validated their findings with human CD4+ and CD8+ CAR-T cells, reporting that in mouse models of lymphoblastic leukemia, treatment with SOCS1-inactivated CAR-T cells produced better tumor control, and the number of CAR-T cells accumulating in bone marrow was twofold higher than it was with unmodified CAR-T cells.
The promise that engineered T-cell therapy holds against various cancers has prompted scientists across the globe to explore ways to enhance its efficacy. A team at the University of Pennsylvania recently proposed inhibiting BET proteins to prevent T-cell exhaustion in CAR-T cell treatment of chronic lymphocytic leukemia, for example.
Scientists at France’s Pasteur Institute found that the interaction between interferon gamma by CAR-T cells and interleukin 12 by host cells is critical to the cancer-killing activity of CAR-T cells. And a team at the Fred Hutchinson Cancer Research Center has designed new CARs with fragments involved in T-cell signaling to increase their ability to recognize tumor antigens.