Abstract Background PD-1 based combination therapies improve survival in advanced renal cell carcinoma (RCC) and urothelial carcinoma (UC), but most patients still experience subsequent disease progression and death. Natural killer (NK) cells are immune effector lymphocytes specialized in the elimination of malignant cells and play an important role in the immune response against RCC and UC. However, prior efforts to develop NK cell-based therapies have been limited by the short half-life of NK cells (10-14 days). Cytokine induced memory-like (CIML) NK cells have prolonged survival, enhanced proliferation, and improved cytotoxicity and prior trials have demonstrated clinical activity in myeloid malignancies and head/neck cancer. Methods We are performing the first study of CIML NK cell therapy among patients with RCC and UC. Patients are eligible who have advanced RCC (including clear cell, chromophobe and translocation RCC) or UC and progression after ≥1 prior treatment regimens, including prior therapy with PD-1/PD-L1 inhibitors. Participants undergo apheresis for autologous NK cell collection followed by fludarabine and cyclophosphamide lymphodepleting chemotherapy. On day 0, patients receive CIML NK cells (which have undergone a 6-day maintenance culture) followed by subcutaneous IL-2 for up to 5 doses to promote CIML NK cell growth and expansion. We plan to enroll 5-10 patients for this pilot study. The primary outcome is feasibility defined as the ability to collect cells, generate product, and administer CIML NK plus 6-day maintenance culture cells to patients. The feasibility endpoint will be met if 60% or more patients are successful per the feasibility criteria. Exploratory objectives will evaluate the safety and efficacy of this regimen. Significance & Vision In this study, we are evaluating the feasibility of treating patients with autologous CIML NK cells. This is the first use of CIML NK cell-based therapy for RCC and UC. Correlative studies will evaluate the phenotype and function of CIML NK cells and determinants of treatment response. This data will inform the development of novel NK cell based therapies in RCC and UC, including NK chimeric antigen receptor strategies. Trial Schema
Xu et al. (Wed,) studied this question.
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