Browsing by Author "Wall, Johanna Tiina Aurora"

Immunotherapies have exponentially gained interest recently as they are less invasive than traditional cancer treatment. Chimeric Antigen Receptor T cell (CAR T) treatment is among the latest breakthroughs and there are currently five FDA and EMA approved CAR T treatments on the market. Despite their potential, CAR T treatment may have serious adverse effects, they are costly, and the suitable patient population is small. In addition, CAR T treatment works best on haematological cancers, with further challenges in treating solid tumours. Treatment safety is a main concern because CAR Ts may start damaging healthy tissue expressing a target antigen, which can be fatal for some patients. The ongoing research on CAR T treatment for solid tumours is prevalent, but none have been approved by FDA or EMA. This study investigated organs from anti-SSEA-4 CAR T treated mice post an in vivo dose-escalating experiment on immunocompromised mice with human ovarian adenocarcinoma (OVCAR4) xenografts. The study included nine treatment groups in total, four dose-escalating treatment groups, three correlating non-tumour treatment groups and both a tumour control and a no-treatment, no-tumour control group. Differences in the tissues regarding the target antigen SSEA-4, non-transduced T cells and SSEA-4 targeted CAR Ts were analysed with H&E and immunostainings. SSEA-4 expression was found in the kidneys, ovarian follicles and in the gastrointestinal muscular layer. In spite of the SSEA-4 expression on healthy tissues, signs of on-target, off-tumour effects were limited in these organs. T cell infiltrates were found mostly in the intestine, stomach, fallopian tubes, and lungs, of which CAR Ts infiltrated specifically the intestine, stomach, and fallopian tubes. Nonetheless, no clear correlation between endemic SSEA-4 expression and CAR T infiltrates was found. Anti-SSEA-4 CAR Ts had an anti-tumour effect on all studied doses. However, some of the high dose mice showed signs of health deterioration. Despite the weak antigen expression on tumours, many immunologically ‘hot’ tumours with lymphocytes were found which proves a successful tumour infiltration. CAR T dose-limiting, and combinatorial target antigens need to be further investigated to improve treatment safety and before advancing into clinical trials.