Your browser doesn't support javascript.
loading
Mesothelin CAR T Cells Secreting Anti-FAP/Anti-CD3 Molecules Efficiently Target Pancreatic Adenocarcinoma and its Stroma.
Wehrli, Marc; Guinn, Samantha; Birocchi, Filippo; Kuo, Adam; Sun, Yi; Larson, Rebecca C; Almazan, Antonio J; Scarfò, Irene; Bouffard, Amanda A; Bailey, Stefanie R; Anekal, Praju Vikas; Montero Llopis, Paula; Nieman, Linda T; Song, Yuhui; Xu, Katherine H; Berger, Trisha R; Kann, Michael C; Leick, Mark B; Silva, Harrison; Salas-Benito, Diego; Kienka, Tamina; Grauwet, Korneel; Armstrong, Todd D; Zhang, Rui; Zhu, Qingfeng; Fu, Juan; Schmidts, Andrea; Korell, Felix; Jan, Max; Choi, Bryan D; Liss, Andrew S; Boland, Genevieve M; Ting, David T; Burkhart, Richard A; Jenkins, Russell W; Zheng, Lei; Jaffee, Elizabeth M; Zimmerman, Jacquelyn W; Maus, Marcela V.
Afiliación
  • Wehrli M; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Guinn S; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Birocchi F; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
  • Kuo A; Cancer Convergence Institute and Bloomberg Kimmel Institute at Johns Hopkins, University, Baltimore, Maryland.
  • Sun Y; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Larson RC; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Almazan AJ; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Scarfò I; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Bouffard AA; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Bailey SR; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Anekal PV; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Montero Llopis P; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Nieman LT; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Song Y; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Xu KH; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Berger TR; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Kann MC; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Leick MB; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Silva H; MicRoN Core, Harvard Medical School, Boston, Massachusetts.
  • Salas-Benito D; MicRoN Core, Harvard Medical School, Boston, Massachusetts.
  • Kienka T; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Grauwet K; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Armstrong TD; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Zhang R; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Zhu Q; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Fu J; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Schmidts A; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Korell F; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Jan M; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Choi BD; Blood and Marrow Transplant Program, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Liss AS; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Boland GM; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Ting DT; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Burkhart RA; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Jenkins RW; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Zheng L; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Jaffee EM; Cellular Immunotherapy Program, Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Zimmerman JW; Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts.
  • Maus MV; Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland.
Clin Cancer Res ; 30(9): 1859-1877, 2024 May 01.
Article en En | MEDLINE | ID: mdl-38393682
ABSTRACT

PURPOSE:

Targeting solid tumors with chimeric antigen receptor (CAR) T cells remains challenging due to heterogenous target antigen expression, antigen escape, and the immunosuppressive tumor microenvironment (TME). Pancreatic cancer is characterized by a thick stroma generated by cancer-associated fibroblasts (CAF), which may contribute to the limited efficacy of mesothelin-directed CAR T cells in early-phase clinical trials. To provide a more favorable TME for CAR T cells to target pancreatic ductal adenocarcinoma (PDAC), we generated T cells with an antimesothelin CAR and a secreted T-cell-engaging molecule (TEAM) that targets CAF through fibroblast activation protein (FAP) and engages T cells through CD3 (termed mesoFAP CAR-TEAM cells). EXPERIMENTAL

DESIGN:

Using a suite of in vitro, in vivo, and ex vivo patient-derived models containing cancer cells and CAF, we examined the ability of mesoFAP CAR-TEAM cells to target PDAC cells and CAF within the TME. We developed and used patient-derived ex vivo models, including patient-derived organoids with patient-matched CAF and patient-derived organotypic tumor spheroids.

RESULTS:

We demonstrated specific and significant binding of the TEAM to its respective antigens (CD3 and FAP) when released from mesothelin-targeting CAR T cells, leading to T-cell activation and cytotoxicity of the target cell. MesoFAP CAR-TEAM cells were superior in eliminating PDAC and CAF compared with T cells engineered to target either antigen alone in our ex vivo patient-derived models and in mouse models of PDAC with primary or metastatic liver tumors.

CONCLUSIONS:

CAR-TEAM cells enable modification of tumor stroma, leading to increased elimination of PDAC tumors. This approach represents a promising treatment option for pancreatic cancer.
Asunto(s)

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Endopeptidasas / Inmunoterapia Adoptiva / Complejo CD3 / Ensayos Antitumor por Modelo de Xenoinjerto / Proteínas Ligadas a GPI / Microambiente Tumoral / Receptores Quiméricos de Antígenos / Mesotelina Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article

Texto completo: 1 Bases de datos: MEDLINE Asunto principal: Neoplasias Pancreáticas / Endopeptidasas / Inmunoterapia Adoptiva / Complejo CD3 / Ensayos Antitumor por Modelo de Xenoinjerto / Proteínas Ligadas a GPI / Microambiente Tumoral / Receptores Quiméricos de Antígenos / Mesotelina Idioma: En Revista: Clin Cancer Res Asunto de la revista: NEOPLASIAS Año: 2024 Tipo del documento: Article