We have previously shown that labyrinthin is expressed on the surface of essentially all adenocarcinomas, including lung, breast, prostate, and colorectal cancer, but not in normal cells. The present work includes further experiments that demonstrate the selective cancer cell surface localization of labyrinthin by FACS analysis of multiple normal, adenocarcinoma, and other (non-adeno) cancer cell lines. In addition, single-cell analysis showed mouse monoclonal anti-labyrinthin antibody MCA 44-3A6 bound to the surface of A549 human lung adenocarcinoma cells, but not to normal WI38 lung fibroblasts. Because available data collectively indicate that labyrinthin is a promising therapeutic target for adenocarcinomas, regardless of tissue origins, several therapeutic strategies targeting labyrinthin are under development, including vaccines against labyrinthin. In the first-in-human clinical trial we demonstrated no toxicity and seroconversion to the vaccine in 5 patients with metastatic lung adenocarcinoma. Using the cloned sequence and computer simulation modeling, a 2nd generation synthetic peptide vaccine was generated, LabVax 3(22)-23 (LabVax), that is comprised of four synthetic peptides to labyrinthin. LabVax incorporates the 1st generation vaccine epitopes with additional labyrinthin-based amino acids to potentiate not only B-cell, but also T-cell responses. LabVax safety was determined in BALB/c mice (male:female 50:50; N=20 per treatment group). A separate study in female C57/BL6 transgenic mice expressing human PD-1/PD-L1 implanted with the murine colon adenocarcinoma cell line MC-38-huPD-L1 also tested for safety, immune responses and anti-tumor effects [LabVax ± mGM-CSF adjuvant, ± pembrolizumab]. Control tumor weights on day 15 were 138 ± 31 mg (x¯ ± SD) and steadily rose across all data collection time points (days 22, 29, 36, 43, 48) up to 1597 ± 577mg by day 48. As expected, pembrolizumab eliminated all tumors by day 29. LabVax + mGM-CSF eliminated the tumor in one mouse by day 29, and significantly (p<0.05) reduced tumor growth in the remaining mice at each time point (day 48 = 884 ± 503mg; N=6). Pembrolizumab increased CD3, CD4, and CD4 cell counts (end of study, day 48), but not LabVax. LabVax alone or in combination with pembrolizumab treatments were well tolerated (no morbidity, mortality, weight loss). The data indicate LabVax is a prototype pan-adenocarcinoma vaccine. A phase I study evaluating the safety of LabVax (± adjuvant) alone or in combination with a PD-1 inhibitor in patients with refractory, metastatic adenocarcinomas is to be conducted at UC Davis Comprehensive Cancer Center. We will also determine the safety of LabVax and the ability of patients to induce an appropriate immune response (e.g., antibody production, T-cell response) against the vaccine.
Citation Format: Michael Babich, James A. Radosevich, Tianhong Li. Generation of peptide vaccines targeting labyrinthin, a pan-adenocarcinoma biomarker [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4583.