Background: Immuno-STATs are novel, modular fusion proteins designed to locally deliver cytokines for the selective activation of tumor-antigen specific CD8+ T cells. CUE-101, the first Immuno-STAT in clinical trials, is composed of a human leukocyte antigen (HLA) complex, HLA-A*0201, a peptide epitope derived from the HPV16 E7 protein, and 4 molecules of reduced affinity human interleukin-2 (IL-2) that is designed to bind, expand, and activate HPV16-specific CD8+ T cells for the treatment of HPV16+ cancers. Methods: CUE-101-01 is an ongoing first-in-human study in HLA-A*0201 patients with HPV16+ recurrent/metastatic head and neck squamous cell carcinoma (R/M HNSCC). Escalating doses of CUE-101 monotherapy or in combination with pembrolizumab was evaluated, followed by expanded enrollment at the recommended phase 2 dose (RP2D). Patients with R/M HNSCC refractory to ≥ 1 platinum- or pembrolizumab-based systemic therapies received CUE-101 monotherapy. Patients with previously untreated PD-L1+ R/M HNSCC received CUE-101 and pembrolizumab 200 mg as first-line treatment. Therapy was administered every 3 weeks until disease progression or toxicity. Objectives included evaluation of safety, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity. Results: As of January 20, 2022, 53 patients received CUE-101 ranging from 0.06 to 8 mg/kg/dose. The most common adverse events included grade ≤ 2 fatigue (40%), anemia (28%), lymphopenia (23%), chills (23%), and hyponatremia (21%). In the monotherapy dose escalation cohort, a MTD was not identified. A RP2D of 4 mg/kg/dose was chosen based on PK, PD, and clinical data in the absence of an MTD. Dose escalation of CUE-101 from 1 to 4 mg/kg in combination with pembrolizumab is ongoing with no DLTs identified as of data cut-off. CUE-101 PK data demonstrated dose-dependent increases in drug exposure that were sustained upon repeat dosing. PD data demonstrated selected expansion of HPV-16 E7_11-20-specific CD8+ T cells, sustained increase in NK cells and transient increase in Treg cells. Of the 14 evaluable patients treated with CUE-101 monotherapy at the RP2D, there was 1 PR and 6 with SD for ≥ 12 weeks. Of the 7 evaluable patients treated with CUE-101 plus pembrolizumab, there were 2 PR (1 confirmed) and 2 with SD for ≥ 12 weeks. Conclusions: CUE-101 is a novel immunotherapeutic that facilitates the targeted delivery of high concentrations of IL-2 to relevant tumor-specific CD8+ T cells. We demonstrate safety and tolerability with encouraging PD signals and antitumor activity. Enrollment continues in the combination cohort. Other novel Immuno-STATs, targeting local delivery of IL-2 for selective expansion and activation of additional tumor-antigen specific T cells, are in development. Clinical trial information: NCT03978689.