Abstract 5643: TCRβ repertoire analysis from a prophylactic MUC1 cancer vaccine trial

Mucin 1 (MUC1) is a large transmembrane glycoprotein that is overexpressed and hypoglycosylated in many adenocarcinomas, including colon cancer. In the hypoglycosylated state, the peptide core of the 20aa variable number of tandem repeats (VNTR) region is exposed, allowing it to function as an altered-self ligand for antibodies and T cells. VNTR peptides have been previously used as antigens in therapeutic cancer vaccines. A clinical trial was conducted to test immunogenicity and safety of a MUC1 100mer VNTR peptide+polyICLC adjuvant vaccine in a prophylactic setting in patients with premalignant colon adenomas who were at high risk for later developing colon cancer. In this premalignant setting, where patients were expected to have fewer immunosuppressive countermeasures usually present in patients with cancer, nearly half of the individuals generated IgG antibodies with no noted adverse effects. Because the antibody response was isotype-switched, it suggested simultaneous T cell activation. To determine whether changes in T cell clonal abundance following immunization could be detected, we sequenced and analyzed TCRβ repertoires from PBMCs of 21 antibody-responders collected before and after both primary and one-year booster vaccinations. Of the patients analyzed, we identified 8 TCRβ sequences from three patients that were significantly elevated after both priming and boosting immunizations, potentially identifying T cell clones that expanded in response to the vaccine. 16 TCRβ sequences from four individuals were significantly decreased at both time points, potentially identifying T cell clones that left circulation to participate in immune responses in secondary lymphoid organs or tissues. The timing of blood collection at two weeks post immunization may have been too late to allow us to detect all of the vaccine-expanded clones before they left circulation. In summary, we found 24 TCRβ CDR3 sequences from 7/21 vaccine responders that significantly changed in frequency after both primary and booster vaccinations. TCR sequencing studies from patients' T cells expanded in vitro with MUC1 peptide will be performed to determine if they overlap with those sequenced ex vivo.

Citation Format: Michelle L. Miller, Jason Lohmueller, John R. McKolanis, Robert Schoen, Olivera J. Finn. TCRβ repertoire analysis from a prophylactic MUC1 cancer vaccine trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5643.