Dilemma of CAR-T cell therapy specific for self-antigens

CAR-T cells are T cells expressing chimeric antigen receptors (CAR). More simply, it is T cells artificially expressing B cell receptors (BCR).

Why would someone design such cells? It is done mainly to bypass MHC restriction requirement, especially in situations when identity of real target antigens are not known. For example, B cell lymphoma is a cancer of B cell origin. This lymphoma cells express tumor-specific antigens that are processed in small pieces, called epitopes, and presented by MHC molecules. But we don’t know a priori what those MHC+epitopes are. So what to do?

Now, we know for certain that B cell lymphoma cells express surface receptors such as CD19 or CD20. These markers are not lymphoma selective, but rather defines B cell cells in general, both normal cells and cancerous cells. So, some scientists thought it would be a good idea to “arm” T cells with receptors specific for self antigens CD19 or CD20. Specificity of these anti-CD19 or anti-CD20 receptors are determined by antigen-interacting portion of immunoglobulin (shortly Ig), since T cell receptor can only see processed antigens, not three-dimensional molecule.

By transducing T cells with anti-CD19 or anti-CD20 receptors CAR-T cells are created. When transferred to lymphoma patient these CAR-T cells will target and eliminate cells expressing either CD19 or CD20. What does it mean? It is obvious that if T cells are successful in their task, patient’s lymphoma cells as well as normal B cells will be eliminated. Depending how long CAR-T cells can persist in patient body, such B cell depletion could last very long time and patient becomes immune deficient, especially if CD19-positive plasma cells are eliminated too. This condition could be remedied by repetitive transfusion of patient with serum (containing Ig) from healthy donors.

Basically, if CAR-T cells are working efficiently then patient becomes immune deficient and if CAR-T cells do not work efficiently then patient’s lymphoma cells would return later. It is unlikely that CAR-T cells could rid of every single lymphoma cells. Effectiveness of CAR-T cells would be based on their memory potential and long-term survival in patient’s body.

So, here is dilemma of CAR-T cells specific for self-antigens.

posted by David Usharauli

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