Researchers Identify Promising Target for CAR T-cell Therapy in Myeloma

Designing CAR T-cells to specifically target GPRC5D — a protein appreciably present on the surface of myeloma cells — may be a safe and effective therapy against multiple myeloma, a preclinical study shows.

The study, “GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells,” was published in the journal Science Translational Medicine.

Chimeric antigen receptor (CAR) T-cell therapy is a type of immunotherapy in which a patient’s T-cells — immune cells with anti-cancer activity — are collected and genetically modified in the lab to recognize specific cancer cell molecules. Once expanded to several million, the modified cells are inserted back into the patient’s body, where they will kill the cancer cells.

CAR T-cell therapies against B-cell mature antigen (BCMA) — a cell surface protein highly produced by myeloma cells — are being evaluated in myeloma patients in several clinical trials (ChiCTR1800018137, NCT03933735, and the UNIVERSAL trial), which are showing promising results.

However, some myeloma cells have low-to-negative levels of BCMA and are not targeted by such therapies, being largely associated with relapse after treatment with BCMA-targeted CAR T-cell therapy. This highlights the need to identify new efficient targets to fight myeloma.

Researchers have now identified a new potential target — GPRC5D — that may overcome this issue.

Several analyses showed that GPRC5D, a cell surface protein, is present only at high levels in myeloma cells and in the hair follicle, which is considered an immune-privileged site (isolated from the actions of the immune system).

High levels of GPRC5D and BCMA were found in similar proportions of myeloma patients, but they are independently produced by myeloma cells. Also, higher levels of GPRC5D in myeloma patients were associated with shorter progression-free survival (the time a patient lives without cancer progression).

The team designed and analyzed several versions of GPRC5D-targeted CAR T-cells, and proceeded to tests with myeloma cells with the version that showed the best response to GPRC5D while interacting exclusively with the target molecule.

The results showed that GPRC5D-targeted CAR T-cells successfully eradicated myeloma cells grown in the lab and in a mouse model. In mice, their anti-cancer effectiveness was superior to that of BCMA-targeted CAR T-cells, and they were able to efficiently eliminate cancer cells resistant to BCMA-targeted therapy.

The team also found that GPRC5D-targeted CAR T-cells were safe in mice and monkeys, with no clinical signs of toxicity, even in the skin and hair (possibly due to its immune-privileged nature).

These findings, along with the preferential presence of GPRC5D in myeloma cells, highlight the use of GPRC5D-targeted CAR T-cells as a potential new therapy for myeloma patients.

“We anticipate that GPRC5D will become an important clinical target for MM [multiple myeloma] immunotherapy,” the researchers wrote.

They also noted that future studies on GPRC5D-targeted CAR T cell therapy should focus on patients with advanced disease, regardless of previous BCMA-targeted therapy. However, they hypothesize patients with low to negative levels of BCMA may benefit from a double CAR T-cell therapy, targeting not only BCMA, but also GPRC5D.