In a groundbreaking leap forward for brain cancer treatment, researchers from the University of Pennsylvania have unveiled promising results from a novel dual-target CAR T cell therapy aimed at recurrent glioblastoma (GBM), one of the most aggressive and lethal brain tumors known to medicine. This innovative approach employs a personalized immunotherapy strategy that harnesses the patient’s own immune cells, genetically engineered to recognize and attack two critical tumor proteins simultaneously. The preliminary data, presented at the 2025 American Society of Clinical Oncology (ASCO) Annual Meeting and published in Nature Medicine, reveal encouraging tumor shrinkage and extended survival in a difficult-to-treat patient population, suggesting new hope where traditional therapies have failed.
CAR T cell therapy has revolutionized hematologic oncology with remarkable success against blood cancers by redirecting immune cells to target malignant cells specifically. However, solid tumors such as glioblastoma have historically resisted such approaches due to their unique microenvironment and immune evasive mechanisms. The Penn team’s breakthrough lies in their dual-targeted CAR T cells, designed to address this challenge by simultaneously engaging two proteins frequently overexpressed in GBM: epidermal growth factor receptor (EGFR) and interleukin-13 receptor alpha 2 (IL13Rα2). This bivalent targeting increases the therapy’s precision and potency, while delivery directly into the cerebrospinal fluid enhances tumor site accessibility.
The clinical trial recruited 18 patients suffering from recurrent GBM, a notoriously resilient cancer that typically recurs within months of standard surgical and adjuvant therapies. All patients underwent maximal tumor resection before receiving an intracerebroventricular infusion of the dual-targeted CAR T cells. Remarkably, among those with measurable tumors post-surgery, nearly two-thirds (62 percent) experienced significant tumor reduction following treatment. While the reduction was often transient, the therapy altered the disease’s natural trajectory, translating into meaningful periods of progression-free survival and quality of life improvements.
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This dual-pronged CAR T cell injection exhibited durability beyond immediate effects, with immune surveillance markers detected in cerebrospinal fluid samples months after infusion. In some instances, CAR T cells remained active for over a year, a testament to the persistent immune engagement against residual tumor cells. One patient, notably, displayed extensive immune cell infiltration—comprised of T cells and macrophages—within tumor tissue excised after relapse, confirming the immune system’s ongoing response driven by the therapy.
These early clinical observations not only reinforce the therapeutic potential of CAR T cells in solid tumor brain neoplasms but also challenge the longstanding assumption that the brain’s immune-privileged status precludes effective immunotherapy. Delivery via cerebrospinal fluid appears to circumvent traditional obstacles like the blood-brain barrier, allowing engineered immune cells direct access to tumor sites. This modality may herald a paradigm shift in treating central nervous system malignancies.
Safety considerations, paramount in any novel therapy, were rigorously monitored, revealing manageable neurotoxicity in over half of the patients at grade 3 severity. Importantly, these adverse events aligned with known side effects of existing FDA-approved CAR T therapies and were effectively managed without introducing unexpected complications. This points to the feasibility of administering such therapies within a controlled clinical setting, balancing efficacy with patient safety.
The study’s findings carry significant implications for the future of GBM treatment. The median survival for patients following recurrence traditionally falls between 6 to 10 months, with few effective options available beyond palliative care. Yet, in this trial, some patients surpassed the one-year survival benchmark, including one individual who maintained stable disease for more than 16 months despite initial advanced tumor spread and aggressive progression. These outcomes advocate for the expansion of clinical investigations, particularly focusing on the application of dual-target CAR T therapy earlier in the disease course.
Researchers aim to optimize therapeutic efficacy by exploring repeat dosing strategies in subsequent trial phases. The current study administered a single infusion, but ongoing efforts seek to determine whether multiple administrations can sustain or enhance tumor control over longer periods. This approach could be transformative, converting temporary remission into durable responses or even long-term remission.
Beyond glioblastoma, this dual-target CAR T platform serves as a proof of concept for multi-antigen targeting in challenging solid tumors, potentially extending to other refractory cancers exhibiting heterogeneous antigen expression. By broadening the immune system’s attack scope, this strategy counters tumor escape pathways that rely on downregulating or mutating single antigen targets.
Academically, this research signifies a milestone in onco-immunology, integrating cutting-edge gene editing, neuro-oncology, and immunotherapy. The work stems from the laboratory of Dr. Donald M. O’Rourke, whose pioneering efforts in neuroimmunotherapy have defined new frontiers in treating brain cancers. Collaboratively, the study aligns with Penn’s commitment to translating laboratory innovations into clinical realities, driving hope for patients confronting otherwise dismal prognoses.
The trial’s momentum, bolstered by support from Kite, a Gilead Company, alongside the Abramson Cancer Center and philanthropic initiatives, underscores the critical role of interdisciplinary and multi-sector partnerships in achieving breakthroughs. As the therapy advances toward trials in newly diagnosed GBM patients, the oncology community eagerly anticipates whether earlier intervention will further enhance outcomes and redefine standards of care for this devastating disease.
In summary, the intracerebroventricular bivalent CAR T cell therapy represents a pioneering stride in confronting recurrent glioblastoma, demonstrating both tumor regression and manageable safety profiles. While further research and larger clinical trials are essential to confirm and broaden these findings, the current data illuminate a promising path towards harnessing the immune system’s power against one of the most formidable cancers afflicting the brain.
Subject of Research: Dual-target CAR T cell therapy for recurrent glioblastoma
Article Title: Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial
News Publication Date: June 1, 2025
Web References:
https://www.pennmedicine.org/treatments/car-t-cell-therapy
https://www.asco.org/annual-meeting
https://www.nature.com/articles/s41591-025-03745-0
https://clinicaltrials.gov/study/NCT06973096
References:
Bagley, S. et al. Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial. Nature Medicine. 2025. DOI: 10.1038/s41591-025-03745-0.
Keywords: Glioblastoma, Brain cancer, CAR T cell therapy, Cancer immunotherapy, Dual-target CAR T, EGFR, IL13Rα2, Immunotherapy, Neuro-oncology, Tumor microenvironment
Tags: aggressive brain tumor therapiesASCO Annual Meeting 2025breakthroughs in brain cancer researchchallenges in solid tumor immunotherapydual protein targeting in cancer therapydual-targeted CAR T cell therapyEGFR and IL13Rα2 targetingglioblastoma treatment advancementsimmune cell engineering for cancerNature Medicine publications on cancer researchpersonalized immunotherapy strategiestumor shrinkage and survival rates