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Salter AI, Rajan A, Kennedy JJ, et al. Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function. Sci Signal. 2021;14(697)doi: 10.1126/scisignal.abe2606.
Salter, A. I., Rajan, A., Kennedy, J. J., Ivey, R. G., Shelby, S. A., Leung, I., Templeton, M. L., Muhunthan, V., Voillet, V., Sommermeyer, D., Whiteaker, J. R., Gottardo, R., Veatch, S. L., Paulovich, A. G., & Riddell, S. R. (2021). Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function. Science signaling, 14(697), . https://doi.org/10.1126/scisignal.abe2606
Salter, Alexander I, et al. "Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function." Science signaling vol. 14,697 (2021). doi: https://doi.org/10.1126/scisignal.abe2606
Salter AI, Rajan A, Kennedy JJ, Ivey RG, Shelby SA, Leung I, Templeton ML, Muhunthan V, Voillet V, Sommermeyer D, Whiteaker JR, Gottardo R, Veatch SL, Paulovich AG, Riddell SR. Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function. Sci Signal. 2021 Aug 24;14(697). doi: 10.1126/scisignal.abe2606. PMID: 34429382; PMCID: PMC8613804.
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Sci Signal. 2021 Aug 24;14(697). doi: 10.1126/scisignal.abe2606.

Comparative analysis of TCR and CAR signaling informs CAR designs with superior antigen sensitivity and in vivo function.

Science signaling

Alexander I Salter, Anusha Rajan, Jacob J Kennedy, Richard G Ivey, Sarah A Shelby, Isabel Leung, Megan L Templeton, Vishaka Muhunthan, Valentin Voillet, Daniel Sommermeyer, Jeffrey R Whiteaker, Raphael Gottardo, Sarah L Veatch, Amanda G Paulovich, Stanley R Riddell

Affiliations

  1. Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. [email protected] [email protected].
  2. Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  3. Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  4. Department of Biophysics, University of Michigan, Ann Arbor, MI 48109, USA.
  5. Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA.
  6. Cape Town HVTN Immunology Laboratory, Hutchinson Centre Research Institute of South Africa, NPC (HCRISA), Cape Town 8001, South Africa.
  7. Department of Medicine, University of Washington School of Medicine, Seattle, WA 98195, USA.

PMID: 34429382 PMCID: PMC8613804 DOI: 10.1126/scisignal.abe2606

Abstract

Chimeric antigen receptor (CAR)-modified T cell therapy is effective in treating lymphomas, leukemias, and multiple myeloma in which the tumor cells express high amounts of target antigen. However, achieving durable remission for these hematological malignancies and extending CAR T cell therapy to patients with solid tumors will require receptors that can recognize and eliminate tumor cells with a low density of target antigen. Although CARs were designed to mimic T cell receptor (TCR) signaling, TCRs are at least 100-fold more sensitive to antigen. To design a CAR with improved antigen sensitivity, we directly compared TCR and CAR signaling in primary human T cells. Global phosphoproteomic analysis revealed that key T cell signaling proteins-such as CD3δ, CD3ε, and CD3γ, which comprise a portion of the T cell co-receptor, as well as the TCR adaptor protein LAT-were either not phosphorylated or were only weakly phosphorylated by CAR stimulation. Modifying a commonplace 4-1BB/CD3ζ CAR sequence to better engage CD3ε and LAT using embedded CD3ε or GRB2 domains resulted in enhanced T cell activation in vitro in settings of a low density of antigen, and improved efficacy in in vivo models of lymphoma, leukemia, and breast cancer. These CARs represent examples of alterations in receptor design that were guided by in-depth interrogation of T cell signaling.

Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

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