PRAME and CTCFL-reactive TCRs for the treatment of ovarian cancer

Abstract

Recurrent disease emerges in the majority of patients with ovarian cancer (OVCA). Adoptive T-cell therapies with T-cell receptors (TCRs) targeting tumor-associated antigens (TAAs) are considered promising solutions for less-immunogenic ‘cold’ ovarian tumors. In order to treat a broader patient population, more TCRs targeting peptides derived from different TAAs binding in various HLA class I molecules are essential. By performing a differential gene expression analysis using mRNA-seq datasets, PRAME, CTCFL and CLDN6 were selected as strictly tumor-specific TAAs, with high expression in ovarian cancer and at least 20-fold lower expression in all healthy tissues of risk. In primary OVCA patient samples and cell lines we confirmed expression and identified naturally expressed TAA-derived peptides in the HLA class I ligandome. Subsequently, high-avidity T-cell clones recognizing these peptides were isolated from the allo-HLA T-cell repertoire of healthy individuals. Three PRAME TCRs and one CTCFL TCR of the most promising T-cell clones were sequenced, and transferred to CD8+ T cells. The PRAME TCR-T cells demonstrated potent and specific antitumor reactivity in vitro and in vivo. The CTCFL TCR-T cells efficiently recognized primary patient-derived OVCA cells, and OVCA cell lines treated with demethylating agent 5-aza-2′-deoxycytidine (DAC). The identified PRAME and CTCFL TCRs are promising candidates for the treatment of patients with ovarian cancer, and are an essential addition to the currently used HLA-A*02:01 restricted PRAME TCRs. Our selection of differentially expressed genes, naturally expressed TAA peptides and potent TCRs can improve and broaden the use of T-cell therapies for patients with ovarian cancer or other PRAME or CTCFL expressing cancers.

The potential value of cancer‐testis antigens in ovarian cancer: Prognostic markers and targets for immunotherapy

“… 64 Rosenberg et al 57 , 112 used TCR‐T targeting MAGE‐A3 to treat a variety of advanced metastatic solid tumors and achieved positive clinical efficacy; they confirmed the efficacy of MHCII‐TCR CD4 T cell therapy targeting MAGE‐A3 and expanded the therapeutic range of TCR‐T for metastatic tumors. Amerongen 72 and colleagues found that the PRAME and CTCFL TCR‐T cells demonstrated potent and specific antitumor reactivity both in vitro and in vivo, the identified PRAME and CTCFL TCRs are promising candidates for the treatment of patients with ovarian cancer. Novel TCR optimization strategies for multiple tumor antigens have been proposed.…”

“…Similarly, the CTCFL TCR‐T cells efficiently recognized ovarian cancer cell lines treated with DAC, implying that pretreatment with DAC may increase the reactivity of transferred TCR‐T cells in patients. 72 Epigenetic regulation not only affects tumor cells but also affects the immune cells of the body. HDAC inhibitors have immune stimulatory effects, and the host immune system also plays an important role in mediating the sustained antitumor response of HDAC inhibitors.…”

The recent advancement of TCR-T cell therapies for cancer treatment

“…Specific TCRs were isolated from allogeneic HLA donors, and TCR-T cell therapy targeting CTCFL has been developed. These TCRs could recognize tumor cells from ovarian cancer patients [54] . The immunoglobulin J chain is overexpressed in multiple myeloma, and TCRs targeting HLA-A*01, A*24, A*03, or A*11-restricted J chain peptides have been discovered.…”

Different origin-derived exosomes and their clinical advantages in cancer therapy

“…Immune checkpoint inhibitors enhance the anti-cancer effect of treatment, thereby blocking the progression of tumors ( 22 ), especially in melanoma, lung cancer, and kidney cancer ( 23 – 25 ). However, the treatment is not effective against all tumor types (e.g., ovarian cancer, prostate cancer, pancreatic cancer, and glioblastoma) because certain tumors are “cold” due to the inability of immune cells to identify cancer cells ( 26 , 27 ). This limits the effectiveness of immune checkpoint inhibitors, thus resulting in poor immune therapy outcomes ( 28 , 29 ).…”