Targeted Treatment for Breast Cancer Explored in New Study

As the scientific community continues to explore whether chimeric antigen receptor (CAR)-based therapy could improve breast cancer survival rates, researchers have outlined the latest research in the disease in a new paper published in Journal of Cellular and Molecular Medicine.

Despite advances and improvements made in the disease, the researchers of the study note that breast cancer still remains one of the top causes of cancer death in women around the world.

“There is an unmet therapeutic necessity to develop effective therapies for breast cancer patients with a high risk of recurrence and metastasis and a low survival rate,” wrote the researchers. “Immunotherapeutic techniques based on CAR-redirected immune cells have evolved, with the potential to redirect immune cells such as T and NK [natural killer] cells to suppress malignancies, with various conducted or ongoing clinical trials.”

A variety of preclinical studies have assessed the potential of CAR T-cell therapy in breast cancer, including those that target MUC1, HER2, EGFR, GD2, and TEM8 antigens. Building on the promise demonstrated in preclinical studies, several first-in-human studies have begun, including a phase 1 study assessing the safety and optimal dose of HER2-targeted CAR T cells in patients with HER2-positive cancers that have brain and/or leptomeningeal metastases.

According to the researchers, most of these clinical trials have been focused on MUC1-targeted CAR T cells. One open-label phase 1 trial, currently recruiting, is assessing the preliminary efficacy of intravenously administered TnMUC1-CAR T cells among patients with advanced TnMUC1-positive breast cancer.

Preclinical studies of CAR NK cells include those targeting HER2/neu, EGFR, L-ICON1, and EpCAM. Data on HER2/neu has been promising, with one murine study showing that intravenous injection of NK-92-scFv(FRP5)-zeta cells led to a reduction in progressive signals 12 hours and 24 hours after injection. HER2/neu-specific CAR NK cells also demonstrated an ability to successfully lyse HER2-expressing MDA-MB468 breast cancer cell lines in vitro.

Some data suggest that EGFR-specific CAR NK cells may be used in patients with triple-negative breast cancer (TNBC) who have elevated EGFR expression. In one study, researchers found that EGFR-CAR NK cells produce cytotoxic and antitumor effects on HS578T, MDA- MB-468, and MDA-MB-231 TNBC cell lines that express upregulated EGFR. The group also saw indications that these CAR NK cells could inhibit the growth of tumors in vivo.

The group also cited data of CAR NK cells targeting tissue factor (TF)—a new surface antigen expressed in 50% to 85% of patients with TNBC—in which TF-targeting CAR NK cells eliminated TF-positive MDA-MB-231 cells in vitro and significantly inhibited tumor growth in vivo.

“Studies on CAR-NK cells collectively deliver a few vital signs for upcoming development,” explained the researchers. “NK-tailored CAR structure appears to be essential for maximizing NK cell toxicity. Also, optimizing a procedure for the expansion and activation of harvested NK cells is required to attain a homogeneous population of clinically substantial counts of memory-like, unexhausted NK cells. Additionally, the utility of CAR-NK cells in the treatment of breast cancer may need further modifications of the NK cells beyond CAR transduction to increase trafficking and desensitize them to the immunosuppressive tumor microenvironment.”

Reference

Nikoo M, Rudiansyah M, Bokov DO, et al. Potential of chimeric antigen receptor (CAR)-redirected immune cells in breast cancer therapies: recent advances. J Cell Mol Med. 2022;26(15):4137-4156. doi:10.1111/jcmm.17465