Dr Forsyth on the Investigation of Intrathecal Dendritic Cells for HER2+/TNBC Leptomeningeal Disease

Peter Forsyth, MD, chairman, Neuro-Oncology Program, Moffitt Cancer Center; professor of oncology, the University of South Florida, discusses the rationale for conducting a first-in-human phase 1 trial (NCT05809752) of dose-escalating intrathecal dendritic cells (cDC1s) targeting HER2/HER3 in patients with leptomeningeal disease from triple-negative breast cancer (TNBC) or HER2-positive breast cancer.

Leptomeningeal disease is a challenging and poorly understood condition, characterized by an inflammatory response, where patients utilize the innate immune system to fight the tumor, Forsyth begins. Although they activate natural killer cells and other innate immune cells, these patients lack a robust adaptive immune response, he notes. Recent insights from single-cell analysis of cell profiles in murine models and human studies, particularly in breast cancer, suggest the necessity of incorporating an adaptive immune response to improve treatment outcomes, Forsyth explains.

This single-arm, non-randomized dose escalation multicenter study was designed to establish the safety of administering intrathecal cDC1s in patients with leptomeningeal disease as well as associations between clinical outcomes & translational cerebrospinal fluid (CSF) studies. This includes single-cell RNA sequencing and cytokine/chemokine arrays, Forsyth states.

The study was supported by preclinical data from murine studies, which demonstrated that cDC1 was safe to be administered intrathecally and produced a Th1-associated adaptive response that cured most mice with HER2-positive leptomeningeal disease and prevented disease recurrence. Accordingly, it was hypothesized that this dendritic cell therapy could increase adaptive immunological responses in the CSF, potentially introducing more effective mechanisms for combating tumor cells, Forsyth says.

The ongoing study will enroll patients at least 18 years of age with HER2-positive disease or TNBC, cytologic or MRI diagnosis of leptomeningeal disease, prior exposure to definitive radiotherapy, and an ECOG performance score of 2 or less. The study's primary end point is to determine the safety and dose-limiting toxicities (DLT) of intrathecal cDC1. Key secondary end points included the proportion of patients surviving at 15 weeks or greater; the association between IFNy and Th1 responses in CSF and serum as well as clinical efficacy outcomes; the amount and activation status of immunocytes or tumor cells in the CSF; and response rates for non–central nervous system tumors according to RANO-LM and RECIST criteria. Patients will receive intrathecal cDC1s once a week for 12 weeks at 1 of 4 dose levels until disease progression, a DLT, or patient withdrawal.