Immunogenic Chemotherapy Enhances Recruitment of CAR-T Cells to Lung Tumors and Improves Antitumor Efficacy when Combined with Checkpoint Blockade

Cancer Cell. 2021 Feb 8;39(2):193-208.e10. doi: 10.1016/j.ccell.2020.11.005. Epub 2020 Dec 24.


Adoptive therapy using chimeric antigen receptor-modified T cells (CAR-T cells) is effective in hematologic but not epithelial malignancies, which cause the greatest mortality. In breast and lung cancer patients, CAR-T cells targeting the tumor-associated antigen receptor tyrosine kinase-like orphan receptor 1 (ROR1) infiltrate tumors poorly and become dysfunctional. To test strategies for enhancing efficacy, we adapted the KrasLSL-G12D/+;p53f/f autochthonous model of lung adenocarcinoma to express the CAR target ROR1. Murine ROR1 CAR-T cells transferred after lymphodepletion with cyclophosphamide (Cy) transiently control tumor growth but infiltrate tumors poorly and lose function, similar to what is seen in patients. Adding oxaliplatin (Ox) to the lymphodepletion regimen activates tumor macrophages to express T-cell-recruiting chemokines, resulting in improved CAR-T cell infiltration, remodeling of the tumor microenvironment, and increased tumor sensitivity to anti-PD-L1. Combination therapy with Ox/Cy and anti-PD-L1 synergistically improves CAR-T cell-mediated tumor control and survival, providing a strategy to improve CAR-T cell efficacy in the clinic.

Trial registration: NCT02706392.

Keywords: CAR-T cells; CXCR3; CXCR6; KP; ROR1; alveolar macrophage; immunogenic cell death; lung adenocarcinoma; oxaliplatin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, Neoplasm / immunology
  • Cell Line
  • Cell Line, Tumor
  • HEK293 Cells
  • Humans
  • Immune Checkpoint Inhibitors / immunology*
  • Immunotherapy, Adoptive / methods
  • Lung Neoplasms / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Receptor Tyrosine Kinase-like Orphan Receptors / immunology
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Chimeric Antigen / immunology*
  • T-Lymphocytes / immunology*
  • Tumor Microenvironment / immunology


  • Antigens, Neoplasm
  • Immune Checkpoint Inhibitors
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen
  • Receptor Tyrosine Kinase-like Orphan Receptors

Associated data