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Regression of renal cell carcinoma by T cell receptor-engineered T cells targeting a human endogenous retrovirus.
Barisic, Stefan; Brahmbhatt, Elizabeth M; Cherkasova, Elena; Spear, Timothy T; Savani, Ujjawal; Pierre, Stephanie; Scurti, Gina M; Chen, Long; Igboko, Muna; Nadal, Rosa; Zeng, Gang; Parry, Gordon; Stroncek, David F; Highfill, Steven; Dalheim, Annika V; Reger, Robert; Nishimura, Michael I; Childs, Richard W.
Afiliación
  • Barisic S; Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Brahmbhatt EM; Department of Surgery, Loyola University Chicago, Chicago, Illinois, USA.
  • Cherkasova E; Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Spear TT; Department of Surgery, Loyola University Chicago, Chicago, Illinois, USA.
  • Savani U; Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Pierre S; Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Scurti GM; Department of Surgery, Loyola University Chicago, Chicago, Illinois, USA.
  • Chen L; Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Igboko M; Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Nadal R; Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Zeng G; T-Cure BioScience, Sherman Oaks, California, USA.
  • Parry G; T-Cure BioScience, Sherman Oaks, California, USA.
  • Stroncek DF; Center for Cellular Engineering, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
  • Highfill S; Center for Cellular Engineering, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, Bethesda, Maryland, USA.
  • Dalheim AV; Department of Surgery, Loyola University Chicago, Chicago, Illinois, USA.
  • Reger R; Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.
  • Nishimura MI; Department of Surgery, Loyola University Chicago, Chicago, Illinois, USA.
  • Childs RW; Laboratory of Transplantation Immunotherapy, Cellular and Molecular Therapeutics Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA childsr@nhlbi.nih.gov.
J Immunother Cancer ; 12(9)2024 Sep 11.
Article en En | MEDLINE | ID: mdl-39266213
ABSTRACT

BACKGROUND:

We discovered a novel human endogenous retrovirus (CT-RCC HERV-E) that was selectively expressed in most clear cell renal cell carcinomas (ccRCC) and served as a source of antigens for T cell-mediated killing. Here, we described the cloning of a novel T cell receptor (TCR) targeting a CT-RCC HERV-E-derived antigen specific to ccRCC and characterized antitumor activity of HERV-E TCR-transduced T cells (HERV-E T cells).

METHODS:

We isolated a CD8+ T cell clone from a patient with immune-mediated regression of ccRCC post-allogeneic stem cell transplant that recognized the CT-RCC-1 HERV-E-derived peptide in an HLA-A11-restricted manner. We used 5'Rapid Amplification of cDNA Ends (RACE) to clone the full length HERV-E TCR and generated retrovirus encoding this TCR for transduction of T cells. We characterized HERV-E T cells for phenotype and function in vitro and in a murine xenograft model. Lastly, we implemented a good manufacturing practice-compliant method for scalable production of HERV-E T cells.

RESULTS:

The HLA-A11-restricted HERV-E-reactive TCR exhibited a CD8-dependent phenotype and demonstrated specific recognition of the CT-RCC-1 peptide. CD8+ T cells modified to express HERV-E TCR displayed potent antitumor activity against HLA-A11+ ccRCC cells expressing CT-RCC HERV-E compared with unmodified T cells. Killing by HERV-E T cells was lost when cocultured against HERV-E knockout ccRCC cells. HERV-E T cells induced regression of established ccRCC tumors in a murine model and improved survival of tumor-bearing mice. Large-scale production of HERV-E T cells under good manufacturing practice conditions generated from healthy donors retained specific antigen recognition and cytotoxicity against ccRCC.

CONCLUSIONS:

This is the first report showing that human ccRCC cells can be selectively recognized and killed by TCR-engineered T cells targeting a HERV-derived antigen. These preclinical findings provided the foundation for evaluating HERV-E TCR-transduced T cell infusions in patients with metastatic ccRCC in a clinical trial (NCT03354390).
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Receptores de Antígenos de Linfocitos T / Retrovirus Endógenos / Neoplasias Renales Límite: Animals / Humans Idioma: En Revista: J Immunother Cancer Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Carcinoma de Células Renales / Receptores de Antígenos de Linfocitos T / Retrovirus Endógenos / Neoplasias Renales Límite: Animals / Humans Idioma: En Revista: J Immunother Cancer Año: 2024 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido