New Approach for the CAR-T Cell Therapy Treatment of Cancer

Research from Osaka University has revealed a new target for the treatment of cancer using monoclonal antibodies (mAbs). The new strategy was discovered by reevaluating the antigens typically targeted by mAb-based treatments using chimeric antigen receptor T-cell (CAR-T) technology, which has proven to be effective in the treatment of solid tumor and blood cancers.

The study, published on Nov. 6, 2017 in Nature, focused on multiple myeloma (MM), a cancer that forms in a type of white blood cell called a plasma cell. The antigens that arise from cancer-specific mutations of cell-surface proteins have been thought to be desirable treatment targets. According to the study, however, the targeting of such antigens is impractical because of the diverse variety of these proteins within and between individual tumors, which makes identifying new cancer-specific target antigens challenging.

Subsequently, the university research team believed new epitopes, which are the part of an antigen recognized by the immune cells, could be determined by searching for cancer-specific mAbs and characterizing the antigens recognized by those mAbs.

According to lead author of the study, Naoki Hosen, in a university press release, the need for advances in treatment resulted from the rate of attributed cancer relapses, which lead to the team applying this new-found strategy to identify novel therapeutic targets for MM.

The team screened more than 10,000 mAb clones known to work against MM and identified MMG49 as a MM-specific mAb specifically recognizing a subset of integrin β7, a cell-surface receptor that enables cell-extracellular matrix adhesion. The study found that MMG49 reacted to MM cells, but did not react to other bone marrow cell types in MM patient samples. This finding drove researchers to design a CAR that includes a fragment derived from MMG49. The resulting MMG49 CAR T was found to have anti-MM effects without damaging normal blood cells.

According to study coauthor Yukiko Matsunaga, in the press release, results also demonstrate that the active conformer of integrin β7 can serve as an immunotherapeutic target against MM, even though the expression of the protein itself is not specific to MM. Matsunaga also explains that these findings support the probability that there are other cancer immunotherapeutic targets that have yet to be identified in many cell-surface proteins that undergo conformational changes, even if the expression of the proteins themselves is not cancer-specific. 

Sources: Nature, Osaka University