First-in-Human Trial Shows Safety of Intraventricular HER2 CAR-T Therapy for Brain Metastases in Breast Cancer
核心洞察
A phase 1 trial demonstrated that intraventricular HER2-directed CAR-T cell therapy (搜索) is safe and feasible for treating HER2-positive breast cancer (搜索) patients with recurrent brain or leptomeningeal metastases (搜索).
The therapy achieved disease stabilization in 44-64% of heavily pretreated patients, with most adverse events being manageable grade 1/2 symptoms like headaches and fatigue.
Correlative studies showed evidence of biological activity, including CAR-T cell persistence in cerebrospinal fluid and gradual disappearance of malignant cells on CSF cytology.
A groundbreaking phase 1 clinical trial has demonstrated the safety and feasibility of delivering HER2-directed CAR-T cell therapy (搜索) directly into the central nervous system for patients with HER2-positive breast cancer (搜索) who developed recurrent brain or leptomeningeal metastases (搜索). The study, led by Jana Portnow, MD, from City of Hope (搜索) and presented at the 2025 Society of Neuro-Oncology Annual Meeting, represents one of the first efforts to test CAR-T cell therapy specifically for breast cancer CNS metastases.
Addressing a Critical Unmet Medical Need
HER2-positive breast cancer (搜索) is known for its propensity to metastasize to the central nervous system, with patients facing particularly poor prognosis when they develop recurrent brain or leptomeningeal disease after radiation or intrathecal chemotherapy. Traditional CAR-T cell therapy has been largely restricted to hematologic cancers, making this approach novel for solid tumor CNS metastases.
The single-center phase 1 trial (NCT03696030) enrolled adults with HER2-positive breast cancer (搜索) (IHC 3+ or FISH amplified) who had recurrent brain metastases (搜索) after radiation or recurrent leptomeningeal metastases (搜索) after intrathecal therapy. Patients were required to have a Karnofsky Performance Status ≥70, with no limit on prior lines of therapy. The heavily pretreated population had received a median of 4-6 prior chemotherapies.
Treatment Design and Dosing Strategy
The study evaluated two treatment approaches: HER2-directed CAR-T cell therapy (搜索) alone (n=10) versus lymphodepletion followed by CAR-T cell therapy (n=13). Lymphodepletion consisted of cyclophosphamide (300 mg/m²/day) and fludarabine (25 mg/m²/day) administered for three consecutive days.
CAR-T cells were administered intraventricularly through an Ommaya reservoir using an escalating dose design across three levels. Dose Level 1 started with 2 × 10⁶ cells in the first cycle, then 10 × 10⁶ cells in subsequent cycles. Dose Level 2 progressed from 10 × 10⁶ to 50 × 10⁶ to 50 × 10⁶ cells, while Dose Level 3, the highest explored level, escalated from 20 × 10⁶ to 100 × 10⁶ to 100 × 10⁶ cells.
Safety Profile Shows Manageable Toxicities
The intraventricular HER2-directed CAR-T cell therapy (搜索) demonstrated a manageable safety profile across both treatment cohorts. The most frequently observed adverse events were low-grade (grade 1/2) symptoms, including headaches, nausea, vomiting, fever, fatigue, and myalgias. These effects typically appeared within the first 24 to 48 hours after each infusion and resolved quickly with supportive care.
Two patients who received lymphodepletion experienced mild immune effector cell-associated neurotoxicity syndrome (ICANS), presenting as transient confusion and lethargy. No higher-grade neurotoxicity was observed. In the lymphodepletion cohort, investigators reported two dose-limiting toxicities—both grade 3 headaches—which prevented patients from receiving all planned CAR-T cell doses.
"This study has shown the initial safety of intraventricular administration of HER2 (搜索)[-directed] CAR T cells alone and with LD," said lead study author Jana Portnow, MD, professor in the Department of Medical Oncology & Therapeutics Research and co-director of the Brain Tumor Program at City of Hope (搜索). "[The addition of] LD did not increase the durability of SD, and we saw an increase in toxicity when LD was added. However, we also saw some evidence of on-target activity when LD was added."
Disease Stabilization Achieved in Heavily Pretreated Patients
Although responses were modest, stable disease was achieved in both treatment groups. In the CAR-T alone cohort, the stable disease rate was 44% with a median duration of 56 days (range 50-136 days). Patients who received lymphodepletion plus CAR-T therapy achieved a higher stable disease rate of 64%, though with the same median duration of 56 days (range 44-134 days).
No partial or complete responses were observed, which investigators noted is expected in a phase 1 CNS CAR-T safety trial. Importantly, patients with stable disease often exhibited clinical stabilization despite being heavily pretreated.
Evidence of Biological Activity
Correlative studies provided important insights into the biological activity of the intraventricular HER2 (搜索)-directed CAR-T cells. Analyses showed that CAR-T cell persistence in the cerebrospinal fluid increased with escalating dose levels and was more pronounced in patients who received lymphodepletion.
In a notable case study of the first patient to receive lymphodepletion prior to CAR-T cell therapy—a 54-year-old woman with HER2 (搜索)-positive, hormone receptor-positive breast cancer involving brain and leptomeningeal metastases (搜索)—investigators detected significant changes in CSF cytology. Prior to her first dose, large, highly atypical cells consistent with metastatic carcinoma were present. After the third dose, only rare large atypical cells remained. After the fourth and fifth doses of CAR-T cell therapy, no malignant cells were detected on CSF cytology.
The therapy triggered measurable rises in pro-inflammatory cytokines in the CSF, such as IL-2 and IFN-γ, reflecting active CAR-T cell engagement with tumor targets. Over time, these cytokines declined while anti-inflammatory cytokines became more prominent, indicating a shift in the immune landscape as the CNS adapted to treatment.
Clinical Implications
This first-in-human study establishes the foundation for further development of intraventricular CAR-T cell therapy for HER2-positive breast cancer (搜索) CNS metastases. The ability to bypass the blood-brain barrier through direct CSF delivery represents a significant advancement for treating these challenging cases. While the addition of lymphodepletion enhanced biological activity markers, it increased toxicity without improving the durability of stable disease, suggesting that optimization of the treatment approach may be needed for future studies.