Saturday, July 25, 2015

6 antigen-specific engineered T cells per µL of blood is needed to protect against multiple myeloma

CAR-T cells express B cell receptors on T cell body. They can target cells expressing proteins. This imposes some limitations on CAR-T cells. Tumors may not express mutated surface proteins readily distinguishable from normal variants. Such differences, however, may be visible at the peptide level. This therapeutic gap could be filled with TCR-engineered T cells targeting tumor-associated MHC+peptide combinations with high affinity and avidity.

New paper in Nature Medicine has provided some early results based on such protocols with NY-ESO-1-specific TCR engineered T cells in multiple myeloma patients. The senior author on this study is Carl June from Upenn whose work on engineered T cells reinvigorated tumor immunotherapy field in recent years.   

Initially, the authors showed that myeloma antigen-specific autologous TCR engineered T cells could persist up to 1 year or more after infusion in patients (though quantification method used here could be unreliable).

Next, the authors showed that lentiviral vector-transduced T cells could migrate and then eliminate myeloma cells from the bone marrow. However, the authors observed that in one patient TCR engineered T cells failed to control myeloma cells once it escaped bone marrow to other tissues. This is concerning. 

In addition, TCR affinity or its expression level in TCR engineered T cells goes dramatically down within 1 year of infusion. This is concerning too.

Finally, the authors claimed that no patients relapsed who had more than 6 antigen-specific T cells per µL of blood. However, close examination of the data also showed that some patients were progression free even though they had less 6 antigen-specific T cells per µL of blood. This implies that T cell number per se  is not a decisive factor here.

In summary, this study showed that close to 70% of patients had a complete or near complete response after TCR-engineered T cell infusion, with minimal associated safety issues.

David Usharauli           

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