Imagine a future where we can harness the power of our own immune cells to fight cancer that has spread to the brain. That future is closer than you think. A groundbreaking study has revealed that CAR T-cell therapy, a revolutionary immunotherapy approach, shows promising early signs of safety and effectiveness in patients with recurrent brain or leptomeningeal metastases from HER2-positive breast cancer. But here’s where it gets even more intriguing: this treatment, when administered directly into the brain’s ventricles, has demonstrated stable disease control in a significant portion of patients, without causing severe side effects.
In a phase 1 trial presented at the 2025 Society of Neuro-Oncology Annual Meeting, researchers explored the use of HER2-directed CAR T-cell therapy, both with and without lymphodepletion (LD), in patients facing this challenging condition. The results? Most patients experienced only mild to moderate side effects, such as headaches, nausea, and fatigue, which typically resolved within 48 hours. While two patients developed confusion and lethargy, possibly related to immune effector cell-associated neurotoxicity, these symptoms were manageable. Interestingly, the addition of LD, a process that reduces existing immune cells to make room for the CAR T-cells, increased toxicity but also showed signs of enhanced anti-cancer activity—a trade-off that sparks debate among experts.
And this is the part most people miss: the study’s design was meticulously crafted to evaluate safety and efficacy at different dose levels, ensuring a comprehensive understanding of how this therapy behaves in the body. Patients received escalating doses of CAR T-cells over multiple cycles, with or without LD, and were closely monitored for side effects, immune response, and disease progression. The results showed that stable disease was achieved in 44% of patients treated with CAR T-cells alone and 64% when combined with LD, though the addition of LD did not significantly extend the duration of disease control.
Lead author Dr. Jana Portnow, a professor at City of Hope, emphasized that while LD increased toxicity, it also provided evidence of on-target activity, suggesting that fine-tuning this approach could maximize benefits while minimizing risks. But here’s the controversial part: should we prioritize reducing toxicity or pushing for greater anti-cancer activity? This question opens the door for further research and debate in the oncology community.
The study’s design included patients with histologically confirmed HER2-positive breast cancer and recurrent brain or leptomeningeal metastases, who