Development and first-in-human CAR T therapy against the pathognomonic MiT-fusion driven protein GPNMB

Abstract CAR T therapy for solid tumors is limited by a lack of safe and uniformly expressed cell-surface targets. Here, we identify the MiT fusion-driven protein GPNMB as being highly, homogeneously, and stably expressed in primary and relapsed translocation-positive alveolar soft part sarcoma (ASPS) and renal cell carcinoma (tRCC). 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.