Currently, the optimal lymphodepletion intensity for peripheral blood mononuclear cell-derived neoantigen-specific CD8 + T cell (Neo-T) therapy has yet to be determined. We report a single-arm, open-label and non-randomized phase 1 study (NCT02959905) of Neo-T therapy with lymphodepletion at various dose intensity in patients with locally advanced or metastatic solid tumors that are refractory to standard therapies. The primary end point is safety and the secondary end points are disease control rate (DCR), progression-free survival (PFS), overall survival (OS). Results show that the treatment is well tolerated with lymphopenia being the most common adverse event in the highest-intensity lymphodepletion groups. Neo-T infusion-related adverse events are only grade 1–2 in the no lymphodepletion group. The median PFS is 7.1 months (95% CI:3.7-9.8), the median OS is 16.8 months (95% CI: 11.9-31.7), and the DCR is 66.7% (6/9) among all groups. Three patients achieve partial response, two of them are in the no lymphodepletion group. In the group without lymphodepletion pretreatment, one patient refractory to prior anti-PD1 therapy shows partial response to Neo-T therapy. Neoantigen specific TCRs are examined in two patients and show delayed expansion after lymphodepletion treatment. In summary, Neo-T therapy without lymphodepletion could be a safe and promising regimen for advanced solid tumors.