Co-expression patterns of chimeric antigen receptor (CAR)-T cell target antigens in primary and recurrent ovarian cancer

• Published in: Gynecologic oncology Vol. 160; no. 2; pp. 520 - 529
• Main Authors: Banville, Allyson C., Wouters, Maartje C.A., Oberg, Ann L., Goergen, Krista M., Maurer, Matthew J., Milne, Katy, Ashkani, Jahanshah, Field, Emma, Ghesquiere, Chanel, Jones, Steven J.M., Block, Matthew S., Nelson, Brad H.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.02.2021
• Subjects: Antigens; Chimeric antigen receptor (CAR)-T cell therapy; High-grade serous ovarian carcinoma; Immunotherapy; Ovarian cancer; Tumor-infiltrating lymphocytes; Antigens; Tumor-infiltrating lymphocytes; Immunotherapy; High-grade serous ovarian carcinoma; Chimeric antigen receptor (CAR)-T cell therapy; Ovarian cancer
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2020.12.005

Chimeric antigen receptor (CAR)-T cell strategies ideally target a surface antigen that is exclusively and uniformly expressed by tumors; however, no such antigen is known for high-grade serous ovarian carcinoma (HGSC). A potential solution involves combinatorial antigen targeting with AND or OR logic-gating. Therefore, we investigated co-expression of CA125, Mesothelin (MSLN) and Folate Receptor alpha (FOLRA) on individual tumor cells in HGSC. RNA expression of CA125, MSLN, and FOLR1 was assessed using TCGA (HGSC) and GTEx (healthy tissues) databases. Antigen expression profiles and CD3+, CD8+ and CD20+ tumor-infiltrating lymphocyte (TIL) patterns were assessed in primary and recurrent HGSC by multiplex immunofluorescence and immunohistochemistry. At the transcriptional level, each antigen was overexpressed in >90% of cases; however, MSLN and FOLR1 showed substantial expression in healthy tissues. At the protein level, CA125 was expressed by the highest proportion of cases and tumor cells per case, followed by MSLN and FOLRA. The most promising pairwise combination was CA125 and/or MSLN (OR gate), with 51.9% of cases containing ≥90% of tumor cells expressing one or both antigens. In contrast, only 5.8% of cases contained ≥90% of tumor cells co-expressing CA125 and MSLN (AND gate). Antigen expression patterns showed modest correlations with TIL. Recurrent tumors retained expression of all three antigens and showed increased TIL densities. An OR-gated CAR-T cell strategy against CA125 and MSLN would target the majority of tumor cells in most cases. Antigen expression and T-cell infiltration patterns are favorable for this strategy in primary and recurrent disease. •CA125, mesothelin and folate receptor alpha showed patchy and partially overlapping expression patterns in ovarian cancer.•An OR-gated CAR strategy against CA125 and mesothelin would target over 90% of tumor cells in over half of cases.•Recurrent HGSC tumors retain expression of CA125, mesothelin, and folate receptor at levels similar to primary tumors.•Recurrent tumors show increased T cell infiltration, suggesting they would be permissive to CAR-T cell entry.