Saturday, July 2, 2016

Improving CAR-T cell anti-tumor selectivity by targeting protein glycoforms

Development of CAR-T cells selectively targeting solid tumors have been challenging due to shared antigenicity between cancerous and healthy tissues. Even minute level of protein [if] expressed on healthy tissue could produce unacceptable side-effects as seen for example in trials with CAR-T cells targeting her2/neu.  

New study in Immunity suggested to target protein glycoforms (here using anti-Tn MUC1 CAR-T cells) instead to avoid cross-targeting of healthy tissue.

The authors speculate that cancer-specific glycosylation could produce cancer-specific glyco-proteins. They found that Tn glycoform of protein mucin 1 (Tn MUC1) is selectively expressed by human T cell leukemia and by many solid tumors and can be specifically detected by CAR-T cells incorporating variable heavy and light chains derived from 5E5 mAb (the University of Copenhagen has patented the 5E5 antibody and antigen epitope and the University of Chicago has filed a patent on the 5E5 CAR).

The authors first tested 5E5BBz CAR-T cells against human Jurkat leukemia cells in vivo in NSG immunodeficient mice and observed that it could double survival of tumor challenged mice.

More importantly, 5E5BBz CAR-T cells were also effective against solid tumor, pancreatic tumor cell line expressing Tn MUC1 glycoform (while the authors reported no side-effects in mice subjected to 5E5BBz CAR-T cells transfer, it is not clear whether human tissue in vivo would express it cryptically).

In summary, the authors believe that targeting glycosylation variants of protein "specifically" expressed on transformed cells could overcome cross-targeting of healthy tissue by CAR-T cells.

David Usharauli

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