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CAR T therapy against the MiTF-driven protein GPNMB [Multiome-Seq]

ABSTRACT: CAR T therapy for solid tumors is constrained by the scarcity of safe, uniformly expressed cell-surface targets. Here we identify GPNMB, a MiT fusion-driven protein, as highly, homogeneously, and stably expressed in primary and relapsed translocation-positive alveolar soft part sarcoma (ASPS) and renal cell carcinoma (tRCC). We develop a GPNMB-directed CAR T cell product, GCAR1, which demonstrates potent activity against patient-matched cells, organoids and xenograft models. In a first-in-human treatment of two patients with relapsed/refractory, metastatic ASPS, GCAR1 is well tolerated and induces stable disease for up to 6 months, accompanied by resolution of many non-target lesions. GCAR1 T cells expand in peripheral blood as a polyclonal population and remain detectable for up to 6 months. Spatial transcriptomics identify multiple immunosuppressive niches adjacent to T cells infiltrating treatment-resistant lesions; biological PDL1 blockade or PD1 and TIGIT double knockout overcomes this resistance and shows synergistic activity with GCAR1 in xenograft models. Taken together, these data provide clinical proof-of-concept for treating solid tumors with CAR T cells targeting a surface antigen driven by an oncogenic gene fusion.

ORGANISM(S): Homo sapiens

PROVIDER: GSE325772 | GEO | 2026/04/02

REPOSITORIES: GEO

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CAR T therapy against the MiTF-driven protein GPNMB

Project description:CAR T therapy for solid tumors is limited by a lack of safe and uniformly expressed cell-surface targets. Here, we identify the MiTF-driven protein GPNMB as being highly, homogeneously, and stably expressed from primary and relapsed translocation-positive alveolar soft part sarcoma (ASPS) and renal cell carcinoma. We developed a GPNMB-targeting CAR T therapy called GCAR1 that shows activity against patient-matched cells, organoids and xenograft models. First-in-human treatment of a patient with metastatic ASPS was well tolerated and generated stable disease until 6 months, with many non-target lesions resolving post-treatment. A polyclonal population of GCAR1 cells expanded in blood and were detectable until 6 months. Spatial transcriptomics revealed multiple immunosuppressive niches in proximity to T cells infiltrating a treatment-resistant lesion, and PDL1 blockade showed synergy with GCAR1 in a xenograft model. Our data provide clinical evidence for treating solid tumors with CAR T cells targeting a surface protein driven by an oncogenic gene fusion.

2026-04-02 | GSE283385 | GEO

GPNMB as a viable CAR Target for MITF pathognomonic fusion-driven cancers: A first-in-person GCAR1 Trial

Project description:CAR T therapy for solid tumours is limited by a lack of safe and uniformly expressed cell-surface targets. We identify the MITF-driven gene GPNMB as being highly, homogeneously and stably expressed from primary and relapsed translocation-positive alveolar soft part sarcoma (ASPS) and renal cell carcinoma (tRCC). We developed a 2nd generation GPNMB-targeting CAR T therapy (GCAR1) that shows activity against cells, organoids and PDX models. First-in-person GCAR1 treatment of a patient with metastatic ASPS was well tolerated and generated stable disease for 6 months, with the majority of non-target lung lesions resolving post-treatment. A diverse population of GCAR1 cells expanded in blood, peaking at 14 days post-treatment. Spatial transcriptomics revealed immunosuppression, including PDL1 expression, in close proximity to T cells infiltrating a treatment-resistant lung lesion, and PDL1 blockade showed synergy with GCAR1 in a PDX model. Our data provide a proof-of-concept for targeting oncogenic translocation-driven genes with CAR T therapy.

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| PRJNA1441496 | ENA

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