A team of researchers at KAIST said on Thursday that they developed a treatment for second-generation T cell receptor-engineered T cells (TCR-T) that overcome the tumor microenvironment for solid cancers where the immune system is suppressed.

First-generation chimeric antigen receptor  T cells, abbreviated as CAR-T cells, showed limited anti-cancer effects but second-generation CAR-T cells with additional signaling molecules have been called "miracle drugs" for their high therapeutic efficacy of more than 80 percent in patients with advanced leukemia. However, these treatments are limited to blood cancers such as B-cell acute leukemia and multiple myeloma, but CAR-T therapies with high therapeutic efficacy for patients with solid tumors still do not exist.

Accordingly, the study led by Professor Kim Chan-hyuk of KAIST's Life Sciences Department used CRISPR-CAS9 gene editing technology to create TCR-T cell therapies that can directly target solid tumors through genetic manipulation. Particularly, the team modified the CD247 gene, a key component of T cell receptor signaling, to include an additional signaling pathway called the telomeric repeat-binding factor 2 (TRF2).

Unlike CARs, which are composed of single proteins, the engineering of additional signaling molecules on TCRs, which form protein complexes, is much more challenging. After various attempts, the researchers succeeded in constructing an optimal TCR module that triggers additional signaling without affecting the formation of the TCR and existing signal transduction.

Consequently, the gene-editing enhanced the proliferation and persistence of TCR-T cells and demonstrated significant anti-cancer effects in a mouse model of malignant melanoma.

"In the immunosuppressive environment of solid cancers, the anti-cancer effect of existing first-generation TCR-T cells is limited but second-generation TCR-T cells are designed to maintain continuous anti-cancer effect even in an immunosuppressive environment," explained Lah Sang-joon, the first author of the study. “We expect this therapy to soon become a necessary treatment for solid cancer patients who are unable to benefit from existing therapies."

The study was published in the latest issue of the Journal for ImmunoTherapy of Cancer.