Targeting B7-H3 in patients with metastatic triple-negative breast cancer and brain metastases: an opportunity to "revive" immunotherapy as a treatment strategy?

Approximately one-third of patients with metastatic triple-negative breast cancer (TNBC) develop brain metastases during their lifetime. Notably, up to 90% of TNBC brain metastases express B7-H3, a molecule that contributes to an immunosuppressive microenvironment-positively correlating with regulatory T cells and negatively with CD8+T cells. We propose that B7-H3-targeted antibody-drug conjugates (ADCs) may help convert these immunologically "cold" tumors into "hot" ones, thereby enhancing the responsiveness of patients with metastatic TNBC and brain metastases to immunotherapy. The ability of ADCs to penetrate a blood-brain barrier that is disrupted by brain metastases and/or associated local therapies generates considerable excitement for this potential approach.We further describe a search of the clinicaltrials.gov website, which yielded eight phase I/II trials examining the efficacy of B7-H3 ADCs, 12.5% (n=1/8) of which exclude patients with brain metastases and 62.5% (n=5/8) of which include patients with asymptomatic brain metastases. Given the natural progression of metastatic TNBC and the high incidence of brain metastases, future studies of B7-H3-targeted therapies should consider the broad inclusion of patients with brain metastases. Additionally, the potential of B7-H3-targeted ADCs to prevent brain metastases warrants investigation in both preclinical models and clinical trials.