FDA Orphan Drug Status Granted for CAR T-Cell Therapy in Malignant Gliomas

• The FDA has granted orphan drug designation to IL13Ra2-targeted chimeric antigen receptor (CAR) T-cells known as MB-101 for recurrent diffuse and anaplastic astrocytoma and glioblastoma (GBM).
• Mustang Bio is developing a novel combination regimen, MB-109, that pairs MB-101 with an oncolytic virus designed to "heat up" the tumor microenvironment and enhance the CAR T cells' efficacy.
• Early clinical data, including complete responses in patients with "hot" tumors treated with IL13Ra2-targeted CAR T cells alone, support the potential of this immunotherapeutic approach, though further funding and clinical evaluation of the combination are critical for progression.

The FDA has granted orphan drug designation to MB-101, IL13Ra2-targeted CAR T cells, for the treatment of recurrent diffuse and anaplastic astrocytoma and GBM. This designation signifies a crucial step in addressing the profound unmet medical needs of patients afflicted with these aggressive and challenging-to-treat primary brain tumors.¹

GBM and high-grade astrocytoma represent some of the biggest challenges in neuro-oncology, characterized by their infiltrative nature, resistance to conventional therapies, and dismal prognoses. Recurrent disease leaves patients with severely limited treatment options and a median overall survival often measured in months.

The FDA's orphan drug designation is specifically conferred upon drugs and biologics intended for the safe and effective treatment, diagnosis, or prevention of rare diseases or disorders affecting fewer than 200,000 patients in the US.² This status provides significant incentives to the developer, including tax credits for clinical trial costs, waivers of prescription drug user fees, and 7 years of market exclusivity upon approval, independent of intellectual property protection. These provisions are designed to derisk and incentivize the development of therapies for small patient populations, where commercial viability might otherwise be challenging.

MB-101, an IL13Ra2-targeted CAR T-cell therapy, targets the interleukin-13 receptor alpha 2 (IL13Rα2), an antigen frequently overexpressed in GBM and astrocytoma.¹ Mustang Bio is strategically advancing a novel therapeutic regimen, designated MB-109, which combines MB-101 with MB-108, an oncolytic virus. This innovative combination strategy is predicated on the concept of reshaping the tumor microenvironment to enhance the efficacy of CAR T-cell therapy.

The oncolytic virus (MB-108), an HSV-1 derived agent, is designed to infect tumor cells, leading to their lysis and, critically, the recruitment of endogenous CD8- and CD3-positive effector T cells. This process aims to transform immunologically "cold" tumors, which typically lack significant immune cell infiltration, into "hot" tumors, thereby creating a more permissive environment for the subsequent infiltration, activation, and tumoricidal activity of the adoptively transferred IL13Ra2-targeted CAR T cells.

Clinical data on the individual components have indicated favorable tolerability profiles. As reported in a 2024 Nature Medicine paper, 2 patients treated solely with MB-101 who exhibited high levels of intratumoral CD3-positive T cells prior to therapy (i.e., "hot" tumors) achieved complete responses lasting 7.5 and over 66 months, respectively.³ These notable responses were observed within a small cohort of patients with the "hottest" tumors among the 57 phase 1 patients evaluable for survival in that publication, underscoring the potential impact of a favorable tumor microenvironment on CAR T-cell effectiveness.

“The goal here was to understand how these cells can target glioblastoma and how they function in the [central nervous system (CNS)],” said Christine Brown, PhD, faculty member in the departments of Hematology & Hematopoietic Cell Transplantation and Immuno-Oncology and investigator on the study, in an interview with Targeted Oncology^TM. “Encouragingly, we showed that local regional delivery of these CAR T cells is both safe and feasible. Importantly, it showed that these CAR T cells can mediate meaningful clinical benefit in a subset of patients…. While the majority of patients ultimately recurred, I think these early clinical findings are encouraging.”

"We are thrilled that MB-101 received orphan drug designation on time and with a designation that is broader than the indication proposed. The orphan drug designation for MB-101, coupled with the orphan drug designation granted previously for MB-108, is strong validation for our science, as we hope to advance MB-101, in combination with MB-108, as a potential treatment option for patients living with malignant glioma, including patients with recurrent glioblastoma and high-grade astrocytomas,” said Manuel Litchman, MD, president and chief executive officer of Mustang Bio, in a press release.¹

REFERENCES:

1. Mustang Bio granted orphan drug designation by U.S. FDA for MB-101 (IL13Ra2-targeted CAR T-cells) to treat astrocytomas and glioblastoma. News release. Mustang Bio. July 7, 2025. Accessed July 8, 2025. https://tinyurl.com/ykyharrf

2. Designating an orphan product: drugs and biological products. US FDA. Updated August 12, 2024. Accessed July 8, 2025. https://tinyurl.com/5ckfaxtv

3. Brown CE, Hibbard JC, Alizadeh D. et al. Locoregional delivery of IL-13Rα2-targeting CAR-T cells in recurrent high-grade glioma: a phase 1 trial. Nat Med. Published online March 7, 2024. doi:10.1038/s41591-024-02875-1