bims-adocet Biomed News
on Adoptive cell therapy
Issue of 2024–10–06
two papers selected by
Shani Kassia Lyskov, Tel Aviv University
  1. CAR-redirected natural killer T cells demonstrate superior antitumor activity to CAR-T cells through multimodal CD1d-dependent mechanisms.
  2. CRISPR/Cas9 editing of NKG2A improves the efficacy of primary CD33-directed chimeric antigen receptor natural killer cells.
  1. Nat Cancer. 2024 Oct 01.
    CAR-redirected natural killer T cells demonstrate superior antitumor activity to CAR-T cells through multimodal CD1d-dependent mechanisms.
    Xin Zhou, Ying Wang, Zhangqi Dou, Gloria Delfanti, Ourania Tsahouridis, Caroline Marnata Pellegry, Manuela Zingarelli, Gatphan Atassi, Mark G Woodcock, Giulia Casorati, Paolo Dellabona, William Y Kim, Linjie Guo, Barbara Savoldo, Ageliki Tsagaratou, J Justin Milner, Leonid S Metelitsa, Gianpietro Dotti.
      Human natural killer T (NKT) cells have been proposed as a promising cell platform for chimeric antigen receptor (CAR) therapy in solid tumors. Here we generated murine CAR-NKT cells and compared them with CAR-T cells in immune-competent mice. Both CAR-NKT cells and CAR-T cells showed similar antitumor effects in vitro, but CAR-NKT cells showed superior antitumor activity in vivo via CD1d-dependent immune responses in the tumor microenvironment. Specifically, we show that CAR-NKT cells eliminate CD1d-expressing M2-like macrophages. In addition, CAR-NKT cells promote epitope spreading and activation of endogenous T cell responses against tumor-associated neoantigens. Finally, we observed that CAR-NKT cells can co-express PD1 and TIM3 and show an exhaustion phenotype in a model of high tumor burden. PD1 blockade as well as vaccination augmented the antitumor activity of CAR-NKT cells. In summary, our results demonstrate the multimodal function of CAR-NKT cells in solid tumors, further supporting the rationale for developing CAR-NKT therapies in the clinic.
    DOI:  https://doi.org/10.1038/s43018-024-00830-0
  2. Nat Commun. 2024 Sep 30. 15(1): 8439
    CRISPR/Cas9 editing of NKG2A improves the efficacy of primary CD33-directed chimeric antigen receptor natural killer cells.
    Tobias Bexte, Nawid Albinger, Ahmad Al Ajami, Philipp Wendel, Leon Buchinger, Alec Gessner, Jamal Alzubi, Vinzenz Särchen, Meike Vogler, Hadeer Mohamed Rasheed, Beate Anahita Jung, Sebastian Wolf, Raj Bhayadia, Thomas Oellerich, Jan-Henning Klusmann, Olaf Penack, Nina Möker, Toni Cathomen, Michael A Rieger, Katharina Imkeller, Evelyn Ullrich.
      Chimeric antigen receptor (CAR)-modified natural killer (NK) cells show antileukemic activity against acute myeloid leukemia (AML) in vivo. However, NK cell-mediated tumor killing is often impaired by the interaction between human leukocyte antigen (HLA)-E and the inhibitory receptor, NKG2A. Here, we describe a strategy that overcomes CAR-NK cell inhibition mediated by the HLA-E-NKG2A immune checkpoint. We generate CD33-specific, AML-targeted CAR-NK cells (CAR33) combined with CRISPR/Cas9-based gene disruption of the NKG2A-encoding KLRC1 gene. Using single-cell multi-omics analyses, we identified transcriptional features of activation and maturation in CAR33-KLRC1ko-NK cells, which are preserved following exposure to AML cells. Moreover, CAR33-KLRC1ko-NK cells demonstrate potent antileukemic killing activity against AML cell lines and primary blasts in vitro and in vivo. We thus conclude that NKG2A-deficient CAR-NK cells have the potential to bypass immune suppression in AML.
    DOI:  https://doi.org/10.1038/s41467-024-52388-1
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