Background: Natural killer (NK) cell therapy is emerging as a promising therapy for patients (pts) with solid tumors and hematologic malignancies with no reported toxicity associated with the cell therapy product itself. NK cell trials in solid tumors are limited by immune inhibitory tumor microenvironments that prevent trafficking and activity of donor NK cells, which is largely governed by TGFβ signaling. We recently developed a novel platform for ex vivo expansion of healthy donor NK cells. We previously showed these cells to be safe in a dose-escalation study when given without cytokine support, with early evidence of response in pts with metastatic colorectal cancer (CRC) and in pts with hematologic malignancies. IL-2 has been well-established as an important activating cytokine supporting NK cells in humans, but can also induce regulatory T cells, which further suppress NK cells by producing TGFβ. We seek to improve upon the early activity we previously observed with NK cells alone by administering concurrently with IL-2 and by limiting the inhibitory tumor microenvironment and regulatory T cells with TGFβ receptor 1 inhibitor vactosertib. Methods: This phase Ib open-label study evaluates the safety and persistence (primary objectives), and the clinical and biological activity and trafficking (secondary objectives) of our novel NK cell therapy in combination with IL-2 (aldesleukin) and TGFβ receptor 1 inhibitor vactosertib. Up to 12 pts with metastatic CRC or relapsed/refractory hematologic malignancies will be enrolled. Pts will undergo low-dose lymphodepletion with fludarabine and cyclophosphamide followed by 2 infusions of NK cells, administered 14 days apart. Concurrently, pts will receive aldesleukin subcutaneously 3 times weekly and vactosertib orally 5 consecutive days/week x4 weeks total. Pts will undergo pre- and post-treatment biopsies for quantification of NK cell trafficking and exploration of immune cell profiling changes in the tumor microenvironment. The trial is currently open to enrollment, with 1 pt accrued at time of submission. Clinical trial information: NCT05400122.