Enhanced AC133-specific CAR T cell therapy induces durable remissions in mice with metastatic small cell lung cancer

Cancer Lett. 2022 Jul 10:538:215697. doi: 10.1016/j.canlet.2022.215697. Epub 2022 Apr 26.


Metastatic small cell lung cancer (SCLC) is not curable. While SCLC is initially sensitive to chemotherapy, remissions are short-lived. The relapse is induced by chemotherapy-selected tumor stem cells, which express the AC133 epitope of the CD133 stem cell marker. We studied the effectiveness of AC133-specific CAR T cells post-chemotherapy using human primary SCLC and an orthotopic xenograft mouse model. AC133-specific CAR T cells migrated to SCLC tumor lesions, reduced the tumor burden, and prolonged survival in a humanized orthotopic SCLC model, but were not able to entirely eliminate tumors. We identified CD73 and PD-L1 as immune-escape mechanisms and combined PD-1-inhibition and CD73-inhibition with CAR T cell treatment. This triple-immunotherapy induced cures in 25% of the mice, without signs of graft-versus-host disease or bone marrow failure. AC133+ cancer stem cells and PD-L1+CD73+ myeloid cells were detectable in primary human SCLC tissues, suggesting that patients may benefit from the triple-immunotherapy. We conclude that the combination of AC133-specific CAR T cells, anti-PD-1-antibody and CD73-inhibitor specifically eliminates chemo-resistant tumor stem cells, overcomes SCLC-mediated T cell inhibition, and might induce long-term complete remission in an otherwise incurable disease.

Keywords: CAR T cells; CD133; CD73; PD-1; SCLC.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • B7-H1 Antigen
  • Cell Line, Tumor
  • Humans
  • Immunotherapy, Adoptive
  • Lung Neoplasms* / pathology
  • Mice
  • Neoplasm Recurrence, Local
  • Small Cell Lung Carcinoma* / pathology
  • Small Cell Lung Carcinoma* / therapy


  • B7-H1 Antigen