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LIGHT enhanced bispecific antibody armed T-cells to treat immunotherapy resistant colon cancer.
Qiao, Guilin; Kone, Lyonell B; Phillips, Evan H; Lee, Steve Seung-Young; Brown, Grace E; Khetani, Salman R; Thakur, Archana; Lum, Lawrence G; Prabhakar, Bellur S; Maker, Ajay V.
Afiliación
  • Qiao G; Department of Surgery, Division of Surgical Oncology, University of California San Francisco, San Francisco, CA, 94143, USA.
  • Kone LB; Department of Surgery, Division of Surgical Oncology, University of Illinois at Chicago, College of Medicine, Chicago, IL, 60612, USA.
  • Phillips EH; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, 60612, USA.
  • Lee SS; Department of Pharmaceutical Sciences, College of Pharmacy, University of Illinois at Chicago, Chicago, 60612, USA.
  • Brown GE; Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA.
  • Khetani SR; Department of Bioengineering, University of Illinois at Chicago, Chicago, IL, 60607, USA.
  • Thakur A; Division of Hematology/Oncology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, USA.
  • Lum LG; Division of Hematology/Oncology, Department of Medicine, University of Virginia Cancer Center, Charlottesville, VA, USA.
  • Prabhakar BS; Department of Microbiology & Immunology, University of Illinois at Chicago, College of Medicine, Chicago, IL, 60612, USA.
  • Maker AV; Department of Surgery, Division of Surgical Oncology, University of California San Francisco, San Francisco, CA, 94143, USA. Ajay.Maker@ucsf.edu.
Oncogene ; 41(14): 2054-2068, 2022 04.
Article en En | MEDLINE | ID: mdl-35177811
Increased tumor infiltrating lymphocytes (TIL) are associated with improved patient responses to immunotherapy. As a result, there is interest in enhancing lymphocyte trafficking particularly to colon cancers since the majority are checkpoint blockade-resistant and microsatellite stable. Here, we demonstrate that activated T-cells (ATC) armed with anti-CD3 x anti-EGFR bispecific antibody increases TIL and mediate anti-tumor cytotoxicity while decreasing tumor cell viability. Furthermore, treatment induces endogenous anti-tumor immunity that resisted tumor rechallenge and increased memory T-cell subsets in the tumor. When combined with targeted tumor expression of the tumor necrosis factor superfamily member LIGHT, activated T-cell proliferation and infiltration were further enhanced, and human colorectal tumor regressions were observed. Our data indicate that tumor-targeted armed bispecific antibody increases TIL trafficking and is a potentially potent strategy that can be paired with combination immunotherapy to battle microsatellite stable colon cancer. SIGNIFICANCE: Enhancing trafficking of tumor infiltrating lymphocytes (TILs) to solid tumors has been shown to improve outcomes. Unfortunately, few strategies have been successful in the clinical setting for solid tumors, particularly for "cold" microsatellite stable colon cancers. In order to address this gap in knowledge, this study combined TNFSF14/LIGHT immunomodulation with a bispecific antibody armed with activated T-cells targeted to the tumor. This unique T-cell trafficking strategy successfully generated anti-tumor immunity in a microsatellite stable colon cancer model, stimulated T-cell infiltration, and holds promise as a combination immunotherapy for treating advanced and metastatic colorectal cancer.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias del Colon / Anticuerpos Biespecíficos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido
Texto completo
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Neoplasias del Colon / Anticuerpos Biespecíficos Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Oncogene Asunto de la revista: BIOLOGIA MOLECULAR / NEOPLASIAS Año: 2022 Tipo del documento: Article País de afiliación: Estados Unidos Pais de publicación: Reino Unido