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

• Published in: Cancer letters 2022-07, Vol.538, p.215697-215697, Article 215697
• Main Authors: Taromi, Sanaz, Firat, Elke, Simonis, Alexander, Braun, Lukas M., Apostolova, Petya, Elze, Mirjam, Passlick, Bernward, Schumacher, Alicia, Lagies, Simon, Frey, Anna, Schmitt-Graeff, Annette, Burger, Meike, Schmittlutz, Katrin, Follo, Marie, von Elverfeldt, Dominik, Zhu, Xuekai, Kammerer, Bernd, Diederichs, Sven, Duyster, Justus, Manz, Markus G., Niedermann, Gabriele, Zeiser, Robert
• Format: Article
• Language: English
• Subjects: Adenosine; Animals; Antibodies; B7-H1 Antigen; Biopsy; Bone cancer; Bone marrow; Bone marrow transplantation; Cancer therapies; CAR T cells; CD133; CD73; CD73 antigen; Cell Line, Tumor; Cell therapy; Chemotherapy; Cytotoxicity; Epitopes; Experiments; Graft-versus-host reaction; Humans; Immunotherapy; Immunotherapy, Adoptive; Life sciences; Lung cancer; Lung Neoplasms - pathology; Lymphocytes; Lymphocytes T; Magnetic resonance imaging; Medical prognosis; Metastases; Metastasis; Mice; Myeloid cells; Neoplasm Recurrence, Local; PD-1; PD-1 protein; PD-L1 protein; Population; Remission; SCLC; Small cell lung carcinoma; Small Cell Lung Carcinoma - pathology; Small Cell Lung Carcinoma - therapy; Software; Statistical analysis; Stem cell transplantation; Stem cells; Tumors; Xenografts
• ISSN: 0304-3835; 1872-7980
• DOI: 10.1016/j.canlet.2022.215697

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. •AC133-specific CAR T cells eliminate cancer stem cells.•Orthotopic SCLC mouse model reflects the clinical course of human metastatic SCLC.•CD73 and PD-L1 expression drives immune-escape mechanisms in human primary SCLC.•The triple-immunotherapy specifically eliminates chemo-resistant tumor stem cells.•The triple-immunotherapy induced cures in 25% of the mice, without signs of GVHD.