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Fully human anti-mesothelin CAR with low immunogenicity for in vivo persistence of anti-tumor engineered T cells

The fully human CAR targets mesothelin, a surface protein overexpressed in several cancer types. P4, a human antibody fragment that binds human mesothelin with high specificity, is fused to T cell signaling domains such as 28z. The T cells engineered to express this CAR are shown to shrink tumors in a mouse model bearing human ovarian tumors overexpressing mesothelin.

Problem:

Though engineered anti-mesothelin chimeric antigen receptor (CAR) T cells show encouraging pre-clinical results against certain cancer types, their clinical efficiency is stunted by their poor long-term persistence in infused human patients.

Indeed, anti-mesothelin CARs are generally designed using mouse antibody fragments, which can trigger a detrimental immune response against the CAR T cells and destroy them (Maus et al, 2014), thus limiting their cancer destroying potential to a narrow time-frame.

Solution:

Instead of using a mouse antibody fragment for engineering CARs, Dr. Powell and his team have produced a fully human anti-mesothelin CAR that shows high cancer killing potential, yet very low immunogenicity.

Advantages:

In vivo persistence of infused CAR T cells after infusion.
Low immunogenicity compared to mouse-derived antibody fragments.
Not inhibited by soluble mesothelin secreted by cancer cells.

Application:

Therapy efficient against mesothelin-expressing tumor cells.

Human ovarian tumor regression in an immunodeficient mouse model. Top panels: Mice infused with fully human anti-mesothelin (P4-28z) CAR T cells show significant regression of ovarian tumor (in color) between day 12 (day of infusion) and day 29. Bottom panels: Mice infused with negative control CD19-28z CAR T cells show ovarian tumor progression (Lanitis et al, 2012).