Efficacy and safety of glycosphingolipid SSEA-4 targeting CAR-T cells in an ovarian carcinoma model.
Hector J MonzoKerttu KalanderMarko M HyytiäinenEndrit ElbasaniJohanna WallLidia Moyano-GalceranJayendrakishore Tanjore RamanathanJoonas J J JukonenPirjo LaakkonenAri RistimäkiJoseph W CarlsonKaisa LehtiSahar SalehiPauli PuolakkainenCaj HaglundHanna SeppänenSirpa LeppaPäivi M OjalaPublished in: Molecular cancer therapeutics (2023)
Chimeric antigen receptor (CAR) T-cell immunotherapies for solid tumors face critical challenges such as heterogeneous antigen expression. We characterized SSEA-4 cell-surface glycolipid as a target for CAR-T cell therapy. SSEA-4 is mainly expressed during embryogenesis but is also found in several cancer types making it an attractive tumor-associated antigen. Anti-SSEA-4 CAR-T cells were generated and assessed pre-clinically in vitro and in vivo for anti-tumor response and safety. SSEA-4 CAR-T cells effectively eliminated SSEA-4 positive cells in all the tested cancer cell lines whereas SSEA-4 negative cells lines were not targeted. In vivo efficacy and safety studies using NSG mice and the high-grade serous ovarian cancer cell line OVCAR4 demonstrated a remarkable and specific anti-tumor response at all the CAR-T cell doses used. At high T cell doses, CAR-T cell-treated mice showed signs of health deterioration after a follow-up period. However, the severity of toxicity was reduced with a delayed onset when lower CAR-T cell doses were used. Our data demonstrate the efficacy of anti-SSEA-4 CAR-T therapy; however, safety strategies, such as dose-limiting and/or equipping CAR-T cells with combinatorial antigen recognition should be implemented for its potential clinical translation.
Keyphrases
- high grade
- cell therapy
- induced apoptosis
- healthcare
- papillary thyroid
- cell cycle arrest
- public health
- cell surface
- oxidative stress
- cell death
- mesenchymal stem cells
- mental health
- adipose tissue
- machine learning
- cell proliferation
- big data
- insulin resistance
- climate change
- bone marrow
- squamous cell
- cancer therapy
- social media
- young adults
- lymph node metastasis
- data analysis
- oxide nanoparticles
- genome wide identification