論文

国際誌
2018年5月2日

Myeloid Conditioning with c-kit-Targeted CAR-T Cells Enables Donor Stem Cell Engraftment.

Molecular therapy : the journal of the American Society of Gene Therapy
  • Yasuyuki Arai
  • ,
  • Uimook Choi
  • ,
  • Cristina I Corsino
  • ,
  • Sherry M Koontz
  • ,
  • Masaki Tajima
  • ,
  • Colin L Sweeney
  • ,
  • Mary A Black
  • ,
  • Steven A Feldman
  • ,
  • Mary C Dinauer
  • ,
  • Harry L Malech

26
5
開始ページ
1181
終了ページ
1197
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1016/j.ymthe.2018.03.003

We report a novel approach to bone marrow (BM) conditioning using c-kit-targeted chimeric antigen receptor T (c-kit CAR-T) cells in mice. Previous reports using anti-c-kit or anti-CD45 antibody linked to a toxin such as saporin have been promising. We developed a distinctly different approach using c-kit CAR-T cells. Initial studies demonstrated in vitro killing of hematopoietic stem cells by c-kit CAR-T cells but poor expansion in vivo and poor migration of CAR-T cells into BM. Pre-treatment of recipient mice with low-dose cyclophosphamide (125 mg/kg) together with CXCR4 transduction in the CAR-T cells enhanced trafficking to and expansion in BM (<1%-13.1%). This resulted in significant depletion of the BM c-kit+ population (9.0%-0.1%). Because congenic Thy1.1 CAR-T cells were used in the Thy1.2-recipient mice, anti-Thy1.1 antibody could be used to deplete CAR-T cells in vivo before donor BM transplant. This achieved 20%-40% multilineage engraftment. We applied this conditioning to achieve an average of 28% correction of chronic granulomatous disease mice by wild-type BM transplant. Our findings provide a proof of concept that c-kit CAR-T cells can achieve effective BM conditioning without chemo-/radiotherapy. Our work also demonstrates that co-expression of a trafficking receptor can enhance targeting of CAR-T cells to a designated tissue.

リンク情報
DOI
https://doi.org/10.1016/j.ymthe.2018.03.003
PubMed
https://www.ncbi.nlm.nih.gov/pubmed/29622475
PubMed Central
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5993968
ID情報
  • DOI : 10.1016/j.ymthe.2018.03.003
  • PubMed ID : 29622475
  • PubMed Central 記事ID : PMC5993968

エクスポート
BibTeX RIS