Abstract P5-08-01: Globo H: A Globo series glycosphingolipid target antigen in breast cancer
Authors: Darren S. Sigal, Apostolia Maria Tsimberidou, I-Ju Chen, Pei Hsu, Tillman Pearce
Journal: Cancer Research (2022)

Abstract Cancer cells may be differentiated from normal cells by the surface expression of unusual glycosylation patterns: tumor-associated carbohydrate antigens (TACAs) may be expressed as membrane-bound glycoproteins or glycolipids. Differential expression of TACAs in multiple cancer types represents a potential therapeutic target for anticancer therapies. At least 16 different types of epithelial cancers have been found to be Globo H–positive, with 60% to 65% of patients with breast cancer having Globo H–positive tumors. It has been shown that tumor-infiltrating lymphocytes in breast cancer tissues could take up Globo H ceramide (GHCer) released by tumor cells masking cancer cells from immune surveillance through the suppression of Notch 1 signaling. Globo series antigens, including Globo H and stage-specific embryonic antigen 4 could associate with the FAK/CAV1/AKT/RIP complex to trigger the downstream β-catenin signaling pathway to promote tumor cell survival. Moreover, exogenous addition of GHCer promoted tumor cell migration. Thus, treatment-mediated depletion of GHCer may overcome the immunosuppressive mechanism of cancer cells, with resulting decreases in tumor cell survival and migration. OBI Pharma, Inc., in collaboration with NeoGenomics, has developed a validated immunohistochemistry assay to measure the expression of Globo H in clinical specimens. The intensity and extent of Globo H expression are determined microscopically using the histochemical scoring system (H-score), defined as the sum of the products of the staining intensity (score of 0-3) multiplied by the percentage of cells (0-100) stained at a given intensity. To date, 420 patients with triple-negative breast cancer (TNBC) have been screened across 4 separate clinical trials. Of those patients, 173 (41%) had an H-score of ≥15, with a median H-score of 70. Of the 173 patients with an H-score of ≥15, 69 (40%) had an H-score of ≥100. Adagloxad simolenin (AS/OBI-822) is a Globo H conjugate vaccine that when administered in combination with the adjuvant OBI-821 results in anti–Globo H IgM and IgG humoral immune responses. These responses have been assessed in all clinical trials of AS/OBI-821 to date. In the early trials that administered up to 9 doses, early and robust IgM responses were noted but with delayed and lower-titer IgG responses. When the number of doses was increased to 9-12 doses over an extended time (up to either 37 or 68 weeks), it became apparent that the peak IgG titers occurred at around the time of the last AS/OBI-821 dose. The time course for the development of anti–Globo H IgM and IgG humoral responses showed that following injection, anti–Globo H IgM and IgG antibody titers demonstrated a geometric mean ratio (GMR) increase of 10.26 and 12.47, respectively, from almost nondetectable levels at baseline. The GMR in the placebo group remained low in comparison. Mean time to peak titer was approximately 4 weeks for IgM and 40 weeks for IgG. These data were employed in the design of the phase 3, randomized, open-label study of the anti–Globo H vaccine AS/OBI-821 in the adjuvant treatment of patients with high-risk, early-stage Globo H–positive TNBC (The GLORIA Study). To enter the GLORIA study, patients must have a centrally confirmed Globo H IHC H-score of ≥15, and it is anticipated that approximately 40% of patients screened will have this level of expression. The GLORIA study is presently enrolling patients in 7 countries, with another 9 countries anticipated to begin recruiting in 2021. Citation Format: Darren S. Sigal, Apostolia Maria Tsimberidou, I-Ju Chen, Pei Hsu, Tillman Pearce. Globo H: A Globo series glycosphingolipid target antigen in breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-08-01.