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Development of novel avenues to overcome challenges facing CAR T cells

  • Soyeon Kim
    Affiliations
    Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
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  • Edmund K. Moon
    Correspondence
    Reprint requests: Edmund K. Moon, University of Pennsylvania/Pulmonary, Stemmler Hall, 2nd Floor, Lab 261 3450 Hamilton Walk, Philadelphia, PA 19104
    Affiliations
    Division of Pulmonary, Allergy, and Critical Care, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pa
    Search for articles by this author
      There has been dramatic success in treating patients with adoptive transfer of autologous T cells genetically modified to express a chimeric antigen receptor redirecting them to the antigen CD19. Despite this success, the application of chimeric antigen receptor T-cell therapy in solid malignancies has encountered many challenges that need to be overcome if similar success across other cancers is to become a reality. These challenges can be classified into 6 categories: the heterogeneity of tumor cell clones and tumor-associated antigen expression; poor T-cell trafficking into the tumor site; poor T-cell survival and persistence; the presence of suppressive immune cells; the secretion of suppressive soluble factors in the tumor microenvironment; and the upregulation of T-cell intrinsic inhibitory pathways. We outline specific representative hurdles in each of these categories and summarize the progress made in understanding them and developing strategies to overcome them.

      Abbreviations:

      AICD (activation-induced cell death), AMP (adenosine monophosphate), APC (antigen-presenting cells), ATP (adenosine triphosphate), CAFs (cancer-associated fibroblasts), CAR (chimeric antigen receptor), CEA (carcinoembryonic antigen), CTLA4 (cytotoxic T-lymphocyte antigen 4), DAG (diacylglycerol), DGK (diacylglycerol kinase), HIF (hypoxia-inducible factor), IDO (indolamine-2,3-dioxygenase), IRs (inhibitor receptors), MDSCs (myeloid-derived suppressor cells), NKTs (natural killer T cells), PD-1 (programmed death receptor 1), PGE2 (prostaglandin E2), SCID (severe combined immunodeficiency), TAAs (tumor-associated antigens), TAMs (tumor-associated macrophages), TANs (tumor-associated neutrophils), TCR (T-cell receptor), TGF-β (transforming growth factor β), TILs (tumor-infiltrating lymphocytes), TME (tumor microenvironment), Tregs (regulatory T cells), TRUCK (T-cell redirected universal cytokine killing), TSA (tumor-specific antigen), VEGF (vascular endothelial growth factor)
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