Phase 1 Trial Explores Intrathecal Dendritic Cells for Leptomeningeal Disease in Breast Cancer

Key Insights

• A phase 1 trial (NCT05809752) is evaluating intrathecal dendritic cells targeting HER2/HER3 in leptomeningeal disease from triple-negative or HER2-positive breast cancer.
• The study uses a 3 + 3 dose-escalation design, administering intrathecal dendritic cells weekly for 12 weeks at doses ranging from 1 x 10^6 to 5 x 10^7 cells.
• Primary endpoints focus on safety and dose-limiting toxicities, while secondary endpoints include survival beyond 15 weeks and immune response markers.

A first-in-human phase 1 trial (NCT05809752) is underway to evaluate the safety and efficacy of intrathecal dendritic cells targeting HER2/HER3 in patients with leptomeningeal disease arising from triple-negative breast cancer (TNBC) or HER2-positive breast cancer. This innovative approach, presented at the 2024 ASCO Annual Meeting, marks the first study exploring intrathecal immune cellular therapy specifically for this rare and challenging condition.

The trial employs a standard 3 + 3 dose-escalation design, starting with a low dose in the initial safety cohort and escalating to four dose levels. Patients receive intrathecal dendritic cells weekly for 12 weeks, with doses ranging from 1 x 10^6 to 5 x 10^7 cells. To be eligible, patients must be 18 years or older, have leptomeningeal disease from TNBC or HER2-positive breast cancer, an ECOG performance status of 3 or lower, and a life expectancy of at least 8 weeks.

Endpoints and Objectives

The primary endpoints of the study are safety and dose-limiting toxicities. Secondary endpoints include survival beyond 15 weeks, response rates, immune response markers such as IFNγ, and the presence and activation status of immunocytes and tumor cells in cerebrospinal fluid. These secondary endpoints aim to provide insights into the immunological effects of the treatment and its potential to control the disease.

Clinical Significance

Leptomeningeal disease, characterized by cancer spreading to the membranes surrounding the brain and spinal cord, presents a significant clinical challenge. Early diagnosis and intervention are critical, as Peter Forsyth, MD, chairman of the Neuro-Oncology Program at Moffitt Cancer Center, notes: "We are lucky that we have seen people quickly and early, so they're still in pretty good shape... it's hard to recognize this disease. It's a huge challenge."

The trial benefits from early patient recruitment, enabling treatment at a less advanced disease stage. Continued data readout from this trial could provide valuable insights into the safety and efficacy of immune cellular therapy in this high-need population.