Photo by Aaron Logan
Lab mice
Researchers say they have identified a multiple myeloma (MM)-specific target for chimeric antigen receptor (CAR) T-cell therapy.
The team unearthed an MM-specific monoclonal antibody (mAb) and designed a CAR that incorporates a fragment derived from that mAb.
The resulting CAR T-cell therapy exhibited anti-MM activity in vitro and in vivo but did not have a negative effect on normal hematopoietic cells.
The researchers described this work in Nature Medicine.
The team believed that new antigen epitopes could be discovered by thoroughly searching for cancer-specific mAbs and characterizing the antigens they recognize.
“We applied this strategy to identify novel therapeutic targets for multiple myeloma . . . ,” explained study author Naoki Hosen, MD, PhD, of Osaka University in Osaka, Japan.
The researchers screened more than 10,000 anti-MM mAb clones and identified MMG49 as an MM-specific mAb that recognizes a subset of integrin β7 molecules.
The team found that MMG49 reacted to MM cells—but not to normal hematopoietic cells—in MM patient samples.
This prompted the researchers to design a CAR that incorporates a fragment derived from MMG49.
When tested in vitro, MMG49 CAR T cells exhibited cytotoxic activity against cell lines expressing the MMG49 epitope and primary MM cell from patients’ bone marrow. However, MMG49 CAR T cells did not have cytotoxic effects on MMG49-negative cells or normal hematopoietic cells.
The researchers said MM cells were completely eradicated by MMG49 CAR T cells. But the therapy did not kill T cells, even when integrin β7 was activated by MAdCAM-1 and CXCL12.
In mouse models of MM, MMG49 CAR T cells significantly prolonged survival when compared to a CD19 CAR T-cell therapy. MMG49 CAR T cells eradicated MM cells and significantly decreased tumor burden in some mice, but some mice relapsed.
MMG49 CAR T cells did not affect normal hematopoietic cells in the mice, and the researchers said there were no unexpected side effects with the treatment.
“Our 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,” said study author Yukiko Matsunaga, PhD, of Princess Margaret Cancer Centre, University Health Network, in Toronto, Canada.
“Therefore, it’s highly plausible 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.”
