An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity Journal Article


Authors: Maus, M. V.; Plotkin, J.; Jakka, G.; Stewart-Jones, G.; Rivière, I.; Merghoub, T.; Wolchok, J.; Renner, C.; Sadelain, M.
Article Title: An MHC-restricted antibody-based chimeric antigen receptor requires TCR-like affinity to maintain antigen specificity
Abstract: Chimeric antigen receptors (CARs) are synthetic receptors that usually redirect T cells to surface antigens independent of human leukocyte antigen (HLA). Here, we investigated a T cell receptor-like CAR based on an antibody that recognizes HLA-A∗0201 presenting a peptide epitope derived from the cancer-testis antigen NY-ESO-1. We hypothesized that this CAR would efficiently redirect transduced T cells in an HLA-restricted, antigen-specific manner. However, we found that despite the specificity of the soluble Fab, the same antibody in the form of a CAR caused moderate lysis of HLA-A2 expressing targets independent of antigen owing to T cell avidity. We hypothesized that lowering the affinity of the CAR for HLA-A2 would improve its specificity. We undertook a rational approach of mutating residues that, in the crystal structure, were predicted to stabilize binding to HLA-A2. We found that one mutation (DN) lowered the affinity of the Fab to T cell receptor-range and restored the epitope specificity of the CAR. DN CAR T cells lysed native tumor targets in vitro, and, in a xenogeneic mouse model implanted with two human melanoma lines (A2+/NYESO+ and A2+/NYESO-), DN CAR T cells specifically migrated to, and delayed progression of, only the HLA-A2+/NY-ESO-1+ melanoma. Thus, although maintaining MHC-restricted antigen specificity required T cell receptor-like affinity that decreased potency, there is exciting potential for CARs to expand their repertoire to include a broad range of intracellular antigens. © 2016 The Author(s).
Journal Title: Molecular Therapy - Oncolytics
Volume: 3
ISSN: 2372-7705
Publisher: Cell Press  
Date Published: 2016-01-01
Start Page: 16023
Language: English
DOI: 10.1038/mto.2016.23
PROVIDER: scopus
PMCID: PMC5904357
PUBMED: 29675462
DOI/URL:
Notes: Article -- Export Date: 6 December 2016 -- Source: Scopus
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MSK Authors
  1. Marcela Valderama Maus
    2 Maus
  2. Michel W J Sadelain
    462 Sadelain
  3. Isabelle C Riviere
    168 Riviere
  4. Jason Plotkin
    11 Plotkin