Development of Anti-Human Mesothelin-Targeted Chimeric Antigen Receptor Messenger RNA–Transfected Peripheral Blood Lymphocytes for Ovarian Cancer Therapy

CD19-targeted chimeric antigen receptor (CAR) engineered T/natural kill (NK)-cell therapies can result in durable clinical responses in B-cell malignancies. However, CAR-based immunotherapies have been much less successful in solid cancers, in part due to ‘on-target off-tumor’ toxicity related to expression of target tumor antigens on normal tissue. Based on preliminary observations of safety and clinical activity in proof-of-concept clinical trials, tumor antigen-specific messenger RNA (mRNA) CAR transfection into selected, activated, and expanded T/NK-cells may permit prospective control of ‘on-target off-tumor toxicity’. To develop a commercial product for solid tumors, we selected mesothelin as an antigen target based on its association with poor prognosis and over-expression in multiple solid cancers. We hypothesized that selecting, activating, and expanding cells ex vivo prior to mRNA CAR transfection would not be necessary, thus simplifying the complexity and cost of manufacturing. We now report th...