GM-CSF disruption in CART cells modulates T cell activation and enhances CART cell anti-tumor activity

Michelle J. Cox, Claudia Manriquez Roman, Erin E. Tapper, Elizabeth L. Siegler, Dale Chappell, Cameron Durrant, Omar Ahmed, Sutapa Sinha, Raphael Mwangi, Nancy S. Scott, Mehrdad Hefazi, Kendall J. Schick, Paulina Horvei, Michael W. Ruff, Ismail Can, Mohamad Adada, Evandro Bezerra, Lionel Aurelien Kankeu Fonkoua, Sameer A. Parikh, Neil E. KayReona Sakemura, Saad S. Kenderian

Research output: Contribution to journalArticlepeer-review


Inhibitory myeloid cells and their cytokines play critical roles in limiting chimeric antigen receptor T (CART) cell therapy by contributing to the development of toxicities and resistance following infusion. We have previously shown that neutralization of granulocyte-macrophage colony-stimulating factor (GM-CSF) prevents these toxicities and enhances CART cell functions by inhibiting myeloid cell activation. In this report, we study the direct impact of GM-CSF disruption during the production of CD19-directed CART cells on their effector functions, independent of GM-CSF modulation of myeloid cells. In this study, we show that antigen-specific activation of GM-CSFKO CART19 cells consistently displayed reduced early activation, enhanced proliferation, and improved anti-tumor activity in a xenograft model for relapsed B cell malignancies. Activated CART19 cells significantly upregulate GM-CSF receptors. However, the interaction between GM-CSF and its upregulated receptors on CART cells was not the predominant mechanism of this activation phenotype. GM-CSFKO CART19 cell had reduced BH3 interacting-domain death agonist (Bid), suggesting an interaction between GM-CSF and intrinsic apoptosis pathways. In conclusion, our study demonstrates that CRISPR/Cas9-mediated GM-CSF knockout in CART cells directly ameliorates CART cell early activation and enhances anti-tumor activity in preclinical models.

Original languageEnglish (US)
Pages (from-to)1635-1645
Number of pages11
Issue number6
StatePublished - Jun 2022

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research


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