CD28 co-stimulatory domain enhances efficacy of CER T cell therapy compared to 4-1BB in an ovarian cancer mouse model

Despite advances in treatment, the 5-year survival rate for late-stage EOC remains low due to factors such as tumor heterogeneity and an immunosuppressive tumor microenvironment (TME). This study investigates the therapeutic potential of chimeric endocrine receptor (CER) T cells engineered to express follicle stimulating hormone (FSH) in a syngeneic mouse model of EOC expressing follicle stimulating hormone receptor (ID8-FSHR).

We compared two different co-stimulatory domains—CD28ζ and 4-1BBζ—in FSH-CER T cells and found that FSH-CD28ζ CER T cells exhibited enhanced cytotoxicity, proliferation, and cytokine secretion in vitro and in vivo. In the ID8-FSHR mouse model, FSH-28ζ CER T cells significantly reduced tumor burden and extended survival compared to FSH-hBBζ and control CER T cells. However, the therapeutic efficacy was compromised by T cell exhaustion, with all FSH-CER T cells expressing high levels of exhaustion markers after 7 days.