New CAR T Approach Shows Early Promise for HER2 Breast Cancer in the Brain

Intraventricular HER2-directed chimeric antigen receptor (CAR) T-cell therapy demonstrated a manageable safety profile and favorable responses in patients with HER2-positive breast cancer. The data are from a single-center, phase 1 trial (NCT03696030).¹

HER2-Positive Breast Cancer and Brain Metastases

HER2-positive breast cancer is one of the more prevalent subtypes of breast cancer, marked by a high risk of recurrence, progression, and development of central nervous system (CNS) brain metastases. Almost 55% of patients with HER2-positive breast cancer will go on to experience CNS brain metastases, underscoring the critical need for advanced therapies.²

As therapies for these patients improve, CNS brain metastases are becoming increasingly more common; however, therapies for CNS brain metastases are limited. Patients with HER2-positive breast cancer whose disease metastasized to the brain are typically limited to surgery, radiation, and some HER2-targeted therapies.²

Emerging data from a phase 1 study suggest that CAR T-cell therapy may be an efficacious option for treatment of HER2-positive breast cancer with CNS metastases. Although CAR T-cell therapy is largely restricted to hematologic cancers, delivery of CAR T cells directly into the cerebrospinal fluid (CFS) via a ventricular system creates a way to bypass the blood–brain barrier to target tumor cells within the CNS.³

Treating HER2-Positive Breast Cancer and CNS Metastases With CAR T-Cell Therapy

The trial investigators enrolled adult patients with HER2-positive breast cancer (IHC 3+ or FISH amplified) who developed recurrent brain metastases or leptomeningeal metastases (LM). Inclusionary criteria consisted of recurrent brain metastases after radiation, recurrent LMs after intrathecal therapy, and a Karnofsky Performance Status of 70 or greater.³

The patients were assigned to 1 or 2 cohorts³:

• HER2-directed CAR T-cell therapy monotherapy
  • Dose level 1 (2 × 10⁶ cells in the first cycle, then 10 × 10⁶ cells in subsequent cycles),
  • Dose level 2 (10 × 10⁶ → 50 × 10⁶ → 50 × 10⁶)
  • Dose level 3 (20 × 10⁶ → 100 × 10⁶ → 100 × 10⁶)
• Lymphodepletion (administered over 3 consecutive days) and CAR T-cell therapy
  • Cyclophosphamide (300 mg/m²/day)
  • Fludarabine (25 mg/m²/day)

The primary end point of the study was safety and tolerability of administering the CAR T cells directly to the CFS. Secondary assessments looked at how long CAR T cells persisted both in the CFS and peripheral blood, durability of stable disease, and median CNS progression-free and overall survival.³

Study Findings

The intraventricular HER2-directed CAR T-cell approach was generally well tolerated in both study cohorts, with most adverse events (AEs) falling into the mild, grades 1 or 2 range. Patients most often reported transient headaches, gastrointestinal discomfort such as nausea or vomiting, low-grade fever, fatigue, and muscle aches. These symptoms tended to arise within a day or 2 after each infusion and typically resolved quickly with routine supportive care.³

A small number of neurological effects were noted. Among patients who underwent lymphodepletion, 2 experienced mild cases of ICANS, characterized by brief periods of confusion and lethargy. No severe or higher-grade neurotoxicity occurred.³

Investigators did identify dose-limiting toxicities in the lymphodepletion cohort: 2 individuals developed grade 3 headaches significant enough to prevent completion of all planned CAR T-cell doses. These findings underscored a clearer toxicity signal when CAR T-cell therapy was administered after lymphodepletion.³

The addition of lymphodepletion increased both the frequency and intensity of AEs but did not appear to extend the duration of stable disease. It did, however, amplify the biological activity of the CAR T cells, leading to stronger indicators of on-target immune engagement and greater CAR T-cell persistence in the CSF.³

Efficacy and Disease Stabilization With CAR T-Cell Therapy

Both cohorts achieved meaningful rates of stable disease (SD). Among patients receiving CAR T cells alone, 44% reached SD with a median duration of 56 days (range, 50–136). In the cohort treated with lymphodepletion followed by CAR T cells, the SD rate rose to 64%, though the median duration remained similar at 56 days (range, 44–134). Notably, many of the patients who stabilized had been heavily pretreated and nonetheless maintained clinical stability during therapy.³

The findings mark a significant milestone in optimizing therapy for patients with HER2-positive breast cancer with CNS brain metastases or LM. Despite the success of HER2-directed therapies, they are often unable to penetrate the blood-brain barrier. The introduction of CAR T cells directly into the CSF represents a novel approach to treating this patient population.

REFERENCES

1. HER2-CAR T cells in treating patients with recurrent brain or leptomeningeal metastases. Clinicaltrials.gov. Updated April 13, 2025. Accessed November 25, 2025. https://clinicaltrials.gov/study/NCT03696030

2. Warrior S, Cohen-Nowak A, Kumthekar P. Modern management and diagnostics in HER2+ breast cancer with CNS metastasis. Cancers (Basel). May 25, 2023. doi: 10.3390/cancers15112908

3. CAR T-Cell therapy for HER2+ breast cancer with CNS metastases. Oncodaily. November 25, 2025. Accessed November 25, 2025. https://oncodaily.com/oncolibrary/car-t-therapy-her