CAR T Therapy Shows Some Significant Responses in High Grade Glioma

Christine Brown, PhD

Credit: City of Hope

MB-101 (Mustang Bio) chimeric antigen receptor (CAR) T-cell therapy was well-tolerated and yielded stable disease or better in 50% of patients with high-grade glioma (HGG), including 2 complete responses (CRs) and 2 partial responses (PRs).¹

“These Phase 1 clinical trial results represent a significant step forward in our understanding of the potential of MB-101 CAR T-cell therapy to treat recurrent GBM, an extremely aggressive tumor with very limited treatment options. One of the main challenges for treating brain cancer is that medications have difficulty crossing the blood-brain barrier. To overcome that barrier, the trial delivered CAR T-cells directly into the brain tumor and the cerebrospinal fluid, the fluid that protects and surrounds the brain and spinal cord. Repetitive locoregional administration of IL13Rα2-CAR T-cells was feasible and well-tolerated with no dose limiting toxicities, even at the highest dose level of 200 x 10⁶ CAR T-cells per infusion. The safety and promising therapy-related bioactivity data pave the way for future studies of MB-101 and offer hope for a transformative treatment approach. We look forward to continuing our work with Mustang on this promising therapy,” lead author Christine Brown, PhD, Heritage Provider Network Professor in Immunotherapy, deputy director of the T-Cell Therapeutics Research Laboratories at City of Hope, said in a statement.²

The trial evaluated MB-101, IL-13Rα2-targeted CAR-T cells, in 65 patients with recurrent high-grade glioma, most of which had grade 4 glioblastoma (GBM) IDH wildtype (n = 41; 72%). Other types of HGG included grade 4 Diffuse midline glioma, H3 K27-altered (n = 2; 4%), Grade 4 Astrocytoma, IDH-mutated (N = 6; 11%), Grade 4 Diffuse astrocytoma not otherwise specified (n = 1; 2%), and grade 3 glioma (n = 7; 12%). The trial evaluated 3 modes of administration, intratumoral (ICT), intraventricular (ICV) and dual ICT/ICV; 2 manufacturing platforms; and 3 doses levels of weekly infusions.¹

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Investigators found that of the 58 patients evaluable for disease response, 29 (50%) achieved stable disease (SD) or better, with 13 (22%) of these responses lasting for over 90 days. Eight of these responses were in patients with grade 4 glioma. Two patients achieved a partial response, and one patient achieved a CR; these patients had IDH-mediated tumors. An additional patient had a CR after additional CAR T cycles off protocol.¹

Investigators observed no dose-limiting toxicities. Common adverse events (AEs) included fatigue, headache, and hypertension with possibly related, serious AEs occurring in 35% (95% CI, 24–48%) of patients. There were possibly related AEs of 1 grade 3 encephalopathy, 1 grade 3 ataxia, and 2 grade 4 cerebral edemas. Increases in central nervous system inflammatory cytokines including IFNγ, CXCL9, and CXCL10 were associated with the therapy. Overall, all routes of delivery had a manageable safety profile at doses up to 200×10⁶ CAR T-cells.¹

In looking at survival, median overall survival (OS) was 8 months. Patients with recurrent GBM that received ICT/ICV delivery of the optimized manufacturing product had a superior median OS of 10.2 months compared with an expected 6 months. Tumors with more of a “hot” tumor environment (TME) correlated with a significant survival benefit compared with those with more of a “cold” TME.¹

“MB-101 has demonstrated compelling therapeutic potential, including delivering unprecedented complete responses in 2 high-grade glioma patients; the first patient who achieved a CR was published in The New England Journal of Medicine. These 2 patients treated solely with MB-101 both had high levels of intratumoral CD3+ T-cells pre-therapy (i.e., “hot” tumors) and achieved complete responses lasting 7.5 and 66+ months, respectively. This trial has led to several other studies using MB-101, including supporting our upcoming novel combination clinical trial of MB-109 [MB-101 (IL-13Rα2 targeted CAR T-cell therapy) + MB-108 (HSV-1 oncolytic virus)] to improve treatment of recurrent GBM and high-grade astrocytoma. The combination leverages initial treatment with MB-108 to reshape the tumor microenvironment and make immunologically “cold” tumors “hot,” thereby potentially enabling the MB-101 CAR T-cell therapy to achieve efficacy equivalent to that seen in intrinsically “hot” tumors in this City of Hope Phase 1 trial,” Manuel Litchman, MD, President and Chief Executive Officer, Mustang, added.²

REFERENCES

1. 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 30, 1001–1012 (2024). doi: 10.1038/s41591-024-02875-1
2. Mustang Bio Announces Publication in Nature Medicine of Data from Phase 1 Trial Evaluating MB-101 IL13Rα2-targeted CAR T-Cells in High-Grade Glioma. News release. Mustang Bio. March 7, 2024. https://www.globenewswire.com/news-release/2024/03/07/2842161/0/en/Mustang-Bio-Announces-Publication-in-Nature-Medicine-of-Data-from-Phase-1-Trial-Evaluating-MB-101-IL13R%CE%B12-targeted-CAR-T-Cells-in-High-Grade-Glioma.html