Background: Labyrinthin (Lab) is a novel tumor-specific protein expressed on the cell surface of the majority of adenocarcinomas of various cancer types. LabVax 3(22)-23 contains 4 synthetic Lab-based peptides designed to elicit both B-cell and T-cell responses. We hypothesized that vaccination against labyrinthin could elicit strong immune responses against Lab-positive adenocarcinomas in cancer patients (pts). This single institution, first-in-human, phase I trial (UCDCC#296) evaluated the feasibility and safety of LabVax 3(22)-23 and adjuvant GM-CSF sargramostim in pts with Lab-positive metastatic or recurrent adenocarcinoma of any primary tumor site after standard-of-care therapies. Methods: Eligible pts were >18 years of age, had metastatic adenocarcinomas of any histology, Lab expression on their tumor cells by immunohistochemistry, adequate end organ function, and performance status (PS) 0-1. Pts received GM-CSF subcutaneously and LabVax 3(22)-23 intradermally on weeks 1, 2, 4, 8, and 12 in the absence of disease progression or unacceptable toxicity. After completion of study treatment, pts were/are followed every 3 months for 1 year. The primary objective was to assess the toxicity per CTCAE V5.0. Dose limiting toxicity (DLT) was defined as grade ≥ 2 allergic and autoimmune reaction, grade ≥ 3 injection site reaction, any grade 3 toxicities lasting >1 week, or any grade ≥ 4 toxicities. Results: All 10 pts were accrued: median (range) age, 52 (34-73) yrs; female/male, 6/4; White/Asians/Hispanic, 7/2/1; PS 1: 100%. Tumor types included colon or rectum (8), ovarian (1), and scalp (1). Median number (range) of prior line systemic therapies, 4 (1-8). The treatment has been well tolerated without any DLT or drug-related severe adverse effect. As of February 10, 2023, 2 pts completed all 5 treatments with stable disease as the best tumor response, and 1 pt is scheduled for last treatment. Seven pts discontinued treatment early due to tumor progression, 3 pts after 4 treatments and 4 pts after 3 treatments. OS has not matured yet. RNA sequencing analysis of peripheral blood mononuclear cells (PBMCs) of first two pts revealed LabVax 3(22)-23 modulated the activity of immune cells and PD-1 pathway. Other correlative studies are ongoing for the effect of LabVax 3(22)-23 on various immune responses (cytokines, anti-Lab antibody production). Conclusions: LabVax 3(22)-23 and GM-CSF were well tolerated in these heavily pre-treated patients with Lab-expressing, refractory adenocarcinomas. Based on preclinical synergism with pembrolizumab, this dose and injection schedule will be tested in a phase II open label study of LabVax 3(22)-23 and GM-CSF in combination with pembrolizumab in patients with refractory lung adenocarcinomas and adenocarcinomas of all other tumor types. Clinical trial information: NCT051013560.