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Background Relapsed or treatment-resistant clear cell renal cell carcinoma (ccRCC) poses a significant unmet medical need, as patients contend with limited therapeutic options and poor clinical prognoses. CD70 is expressed in the majority of ccRCC and presents an attractive target for chimeric antigen receptor T cell (CAR-T) therapy.While CAR-T therapies have revolutionized the treatment of hematologic malignancies, this success has not been replicated in solid tumor indications. The hostile tumor microenvironment (TME) that CAR-T cells encounter in solid tumors is thought to be a main contributor to this lack of efficacy, driven by metabolic stress, immunosuppression, and T cell exhaustion.IB-T101, an autologous CAR-T targeting CD70 in ccRCC, is expanded under OUTLAST™ conditioning to address the challenges of the solid tumor TME. OUTLAST™ conditioning emulates key features of the TME during CAR-T expansion, resulting in CAR-T products that exhibit an early memory T cell phenotype, are resistant to suppressive signals from the TME, and exhibit increased persistence. The effects of OUTLAST™ conditioning are expected to lead to superior clinical outcomes for IB-T101 CAR-T cells in the ccRCC solid tumor setting.Methods Here we report an in-progress phase 1, first-in-human, open label, investigator-initiated clinical trial ( NCT06819293) aimed at evaluating the safety and preliminary efficacy of IB-T101 in ccRCC. Patients eligible for inclusion had previously relapsed following VEGF targeting therapies alone or in combination with an immune checkpoint inhibitor. Autologous patient T cells are transduced with a lentiviral vector encoding a CD70-targeting CAR and are CRISPR Cas9 gene edited to knock out endogenous CD70, followed by expansion under OUTLAST™ conditioning. Escalating doses of IB-T101 CAR-T cells (150 – 500 x 106) are infused following lymphodepletion. Primary endpoints of the study will assess the safety and tolerability of IB-T101. Additional objectives of the study are to assess the anti-tumor activity and the pharmacokinetics of IB-T101. Correlative assessments will include pre-treatment biopsies to assess the level of CD70 expression in the tumor.Trial Registration NCT06819293Ethics Approval The study was approved by the Tongji Hospital Medical Ethics Committee, ID TJ-IRB202412051-1. Study participants gave informed consent before enrolling in the study.